dihydropyridines has been researched along with Disease-Models--Animal* in 148 studies
7 review(s) available for dihydropyridines and Disease-Models--Animal
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Molecular Mechanism of Dihydropyridine Ca
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Disease Progression; Humans; Hypertension, Pulmonary; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Nicardipine; Pulmonary Artery; Rats; Receptors, Calcium-Sensing; Up-Regulation; Vascular Remodeling; Vasoconstriction | 2016 |
Physiological significance of delayed rectifier K(+) channels (Kv1.3) expressed in T lymphocytes and their pathological significance in chronic kidney disease.
T lymphocytes predominantly express delayed rectifier K(+) channels (Kv1.3) in their plasma membranes. More than 30 years ago, patch-clamp studies revealed that the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. In addition to selective channel inhibitors that have been developed, we recently showed physiological evidence that drugs such as nonsteroidal anti-inflammatory drugs, antibiotics, and anti-hypertensives effectively suppress the channel currents in lymphocytes, and thus exert immunosuppressive effects. Using experimental animal models, previous studies revealed the pathological relevance between the expression of ion channels and the progression of renal diseases. As an extension, we recently demonstrated that the overexpression of lymphocyte Kv1.3 channels contributed to the progression of chronic kidney disease (CKD) by promoting cellular proliferation and interstitial fibrosis. Together with our in-vitro results, the studies indicated the therapeutic potency of Kv1.3-channel inhibitors in the treatment or the prevention of CKD. Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Electrophysiological Phenomena; Humans; Immunologic Factors; Kidney; Kv1.3 Potassium Channel; Leukocytes; Macrolides; Membrane Potentials; Renal Insufficiency, Chronic; T-Lymphocytes | 2015 |
Gene and stem cell therapy in ischemic stroke.
Possible strategies for treating ischemic stroke include neuroprotection (preventing injured neurons from undergoing apoptosis in the acute phase of cerebral ischemia) and stem cell therapy (the repair of disrupted neuronal networks with newly born neurons in the chronic phase of cerebral ischemia). First, we estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by administration of GFNF protein. GDNF protein showed a direct protective effect against ischemic brain damage. Pretreatment of animals with adenoviral vector containing GDNF gene (Ad-GDNF) 24 h before the subsequent transient middle cerebral artery occlusion (MCAO) effectively reduced infarcted volume. Secondly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin. Both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their antioxidative property. Lastly, we developed a restorative stroke therapy with a bioaffinitive scaffold, which is able to provide an appropriate platform for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes. Topics: Animals; Antioxidants; Azetidinecarboxylic Acid; Biliverdine; Brain Ischemia; Dihydropyridines; Disease Models, Animal; Genetic Therapy; Glial Cell Line-Derived Neurotrophic Factor; Humans; Models, Biological; Neuroprotective Agents; Stem Cell Transplantation | 2009 |
Angiotensin converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension.
In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement. Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Meta-Analysis as Topic; Nifedipine; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Dysfunction, Left | 2002 |
Lacidipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of hypertension.
Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension. Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution | 1994 |
Do calcium channel blockers have renal protective effects?
Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease, and in renal transplant recipients with or without cyclosporin therapy. In general, studies in animal models of hypertension and in hypertensive humans have demonstrated reduction in renal vascular resistance, and preservation or enhancement of renal plasma flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have also demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well-suited for the treatment of patients with hypertensive disease even in the presence of renal impairment, a clinical scenario common in the elderly population. Topics: Aging; Animals; Calcium Channel Blockers; Clinical Trials as Topic; Cyclosporine; Diabetic Nephropathies; Dihydropyridines; Diltiazem; Disease Models, Animal; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Transplantation; Rats; Rats, Inbred SHR; Verapamil | 1994 |
Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia.
Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) exist in cardiac tissue and a potential role in the pathogenesis of myocardial ischemia was hypothesized early after their discovery. Studies in in vitro models of myocardial ischemia and reperfusion have indicated that KATP openers, as a class, exert protective effects. This has been assessed by determination of recovery of contractile function, inhibition of contracture, or inhibition of necrosis. This protective effect appears to be exerted directly on the myocardium and is not dependent on peripheral or coronary dilator activities. These protective effects are uniformly abolished by blockers of KATP. The protective effects of KATP openers are accompanied by a conservation of myocardial energy during ischemia, and this occurs despite a relative lack of cardiodepressant effects. In vivo studies have shown more variable results with some investigators showing efficacy and others not showing efficacy. The lack of efficacy for some investigators may be related to the potent vasodilator activity of the KATP openers used. Efficacy for KATP openers has been shown in canine models of infarction and stunned myocardium. KATP blockers also appear to abolish the protective effects of KATP openers in these models. Future work on KATP openers is focused on the determination of the molecular mechanism of action for the cardioprotective effects of these agents, development of tissue selectivity, and the importance of action potential shortening in mediating cardioprotection. Topics: Action Potentials; Adenosine Triphosphate; Animals; Benzopyrans; Cromakalim; Dihydropyridines; Disease Models, Animal; Dogs; Guanidines; Guinea Pigs; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Picolines; Pinacidil; Potassium Channels; Pyrans; Pyrroles; Rats; Vasodilator Agents | 1994 |
1 trial(s) available for dihydropyridines and Disease-Models--Animal
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Lacidipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of hypertension.
Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension. Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution | 1994 |
141 other study(ies) available for dihydropyridines and Disease-Models--Animal
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Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy.
Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8 Topics: Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; CD47 Antigen; Cell Line, Tumor; Cricetinae; Dihydropyridines; Disease Models, Animal; Drug Repositioning; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Immunotherapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Targeted Therapy; Neoplasms; Receptors, Immunologic; Receptors, Virus; T-Lymphocytes | 2021 |
An antihypertensive agent benidipine is an effective neuroprotective and antiepileptic agent: an experimental rat study.
Benidipine is an L, N and T type calcium channel blocker drug that is widely used as an antihypertensive drug.. For the first time in the literature, it was aimed to investigate the effectiveness of benidipine in controlling epileptic seizure and preventing the development of neurodegeneration in epilepsy.. An experimentally epilepsy model was produced with pentylenetetrazole, and rats were divided into seven groups, in different benidipine treatment doses or with valproic acid combinations. The epileptic activities of all rats were recorded according to the Fisher&Kittner classification. Biochemical parameters, histopathological Caspase-3 activity, Wyler hippocampal sclerosis, gliosis and neuronal degenerations were investigated.. It was found that in the post-hoc analysis of epileptic activities, there was a similar antiepileptic scores among the treatment groups. IL-1 level was found to be significantly lower in the benidipine 4 mg/kg group, and TNF-alpha was lower in the group given valproic acid+benidipine 2 mg/kg (p<0.05). The other biochemical parameters were not found to be significant. Neural degeneration levels in the brain tissues were statistically significant (p<0.001). Compared with the healthy group, the most neural degeneration was in the control group, the least neural degeneration was in the valproic acid+benidipine 4 mg/kg group.. For the first time in the literature, benidipine, alone or combined with valproic acid, were found to have a statistically significant antiepileptic efficacy, and provided neuroprotection when combined with valproic acid. Benidipine will be a promising agent in the treatment of epilepsy with its antiepileptic and neuroprotective effects. Topics: Animals; Anticonvulsants; Antihypertensive Agents; Brain; Dihydropyridines; Disease Models, Animal; Male; Neuroprotective Agents; Rats; Rats, Wistar; Valproic Acid | 2021 |
Investigating the potential of utilizing glycerosomes as a novel vesicular platform for enhancing intranasal delivery of lacidipine.
Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine. Topics: Administration, Intranasal; Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Disease Models, Animal; Drug Compounding; Drug Liberation; Glycerol; Hypertension; Liposomes; Male; Methylprednisolone Acetate; Nasal Absorption; Nasal Mucosa; Permeability; Phosphatidylcholines; Rats, Wistar; Solubility | 2020 |
Comparison of effects of L/N-type and L-type calcium channel blockers on post-infarct cardiac remodelling in spontaneously hypertensive rats.
Hypertension and coronary events are becoming more prevalent in aging societies, and myocardial infarction usually occurs in calcium channel blocker (CCB)-treated hypertensive patients. We herein compared the effects of cilnidipine, an L/N-type CCB and amlodipine, an L-type CCB, on post-infarct left ventricular (LV) remodelling in spontaneously hypertensive rats (SHRs). Male SHRs were subjected to 30 minutes of left coronary artery occlusion followed by reperfusion (MI group). The administration of cilnidipine (10 mg/kg/d; MI + Cil group) or amlodipine (10 mg/kg/d; MI + Aml group) was initiated one week before surgery and continued for five weeks. Both CCBs decreased blood pressure. Four weeks after surgery, cilnidipine, but not amlodipine, attenuated LV dilatation, fractional shortening impairments, end-diastolic pressure elevations, and tau elongation. In the non-infarct region, myocyte hypertrophy and brain natriuretic peptide (BNP) mRNA levels were similarly attenuated by both CCBs. On the other hand, interstitial fibrosis, the mRNA expression of collagen type III and transforming growth factor (TGF) β and immunohistological TGF β protein expression in the non-infarct region were reduced more in the MI + Cil group than in the MI + Aml group. Additionally, elevated angiotensin-converting enzyme activity and interstitial noradrenaline concentrations in the non-infarct region were reduced by cilnidipine. These results suggest that cilnidipine reduced cardiac noradrenaline concentrations and inhibited the renin-angiotensin system, which attenuated post-infarct remodelling more than amlodipine in hypertensive rats. Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hypertension; Male; Myocardial Infarction; Norepinephrine; Rats, Inbred SHR; Renin-Angiotensin System; Ventricular Function, Left; Ventricular Remodeling | 2020 |
Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Na
Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Na. We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3 mg/kg once a day for 3 weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force.. Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results.. These in vivo results in the well characterized Tcf4(± ) PTHS mice may suggest the potential to test this already approved drug further in a clinical study with PTHS patients or suggest the potential for use off label under compassionate use with their physician. Topics: Animals; Behavior Control; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Drug Discovery; Drug Repositioning; Facies; Fear; Gene Expression Regulation; Humans; Hyperventilation; Intellectual Disability; Male; Mice; NAV1.8 Voltage-Gated Sodium Channel; Nicardipine; Phenotype; Social Skills; Transcription Factor 4 | 2020 |
Deferiprone and efonidipine mitigated iron-overload induced neurotoxicity in wild-type and thalassemic mice.
We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition.. Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month.. HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine.. These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition. Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Deferiprone; Dihydropyridines; Disease Models, Animal; Iron; Iron Chelating Agents; Iron Overload; Mice; Mice, Inbred C57BL; Neurotoxicity Syndromes; Nitrophenols; Organophosphorus Compounds; Thalassemia | 2019 |
An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation.
Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC inhibition on such remodelling is unknown. Here, we investigated the ability of a clinically available Ca2+-channel blocker (CCB) with NTCC-blocking activity to suppress the arrhythmogenic effects of AF-promoting remodelling in dogs.. Mongrel dogs were kept in AF by right atrial tachypacing at 600 bpm. Four groups were studied under short-term AF (7 days): (i) Shams, instrumented but without tachypacing (n = 5); (ii) a placebo group, tachypaced while receiving placebo (n = 6); (iii) a control tachypacing group receiving nifedipine (10 mg orally twice-daily; n = 5), an L-type CCB; and (iv) a cilnidipine group, subjected to tachypacing and treatment with cilnidipine (10 mg orally twice-daily; n = 7), an N-/L-type CCB. With cilnidipine therapy, dogs with 1-week AF showed significantly reduced autonomic changes reflected by heart rate variability (decreases in RMSSD and pNN50) and plasma norepinephrine concentrations. In addition, cilnidipine-treated dogs had decreased extracellular matrix gene expression vs. nifedipine-dogs. As in previous work, atrial fibrosis had not yet developed after 1-week AF, so three additional groups were studied under longer-term AF (21 days): (i) Shams, instrumented without tachypacing or drug therapy (n = 8); (ii) a placebo group, tachypaced while receiving placebo (n = 8); (iii) a cilnidipine group, subjected to tachypacing during treatment with cilnidipine (10 mg twice-daily; n = 8). Cilnidipine attenuated 3-week AF effects on AF duration and atrial conduction, and suppressed AF-induced increases in fibrous-tissue content, decreases in connexin-43 expression and reductions in sodium-channel expression.. Cilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion. Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function, Left; Atrial Remodeling; Calcium Channel Blockers; Calcium Channels, N-Type; Calcium Signaling; Connexin 43; Dihydropyridines; Disease Models, Animal; Dogs; Fibrosis; Heart Atria; Heart Rate; Presynaptic Terminals; Sodium Channels; Sympathetic Nervous System | 2019 |
Platelet-Activating Factor (PAF) Receptor Antagonism Modulates Inflammatory Signaling in Experimental Uveitis.
The phospholipid mediator platelet-activating factor (PAF) activates an inflammatory response that includes arachidonic acid release and prostaglandin production in the eye, increasing vascular permeability and inflammation. The purpose of this study is to investigate the action of LAU-0901, a novel PAF receptor antagonist, on experimental uveitis.. Uveitis was induced in Lewis rats by lipopolysaccharide treatment. LAU-0901 was then delivered systemically in different concentrations at plus 4 and 16 hours, or vehicle injected as controls. Additional animals were used for histological analyses of untreated, uveitis, and uveitis-plus-LAU-0901 retinas. Conventional histological and immunohistochemical methods were employed. A slit lamp and Spectral Domain-Ocular Coherence Tomography (SD-OCT) retinal imager was used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 hours after the second LAU-0901 injection in this 24-hour model. Aqueous humor was collected and quantified, and also analyzed for tumor necrosis factor alpha (TNF-α).. Uveitic eyes demonstrated hypopyon formation, leukocyte infiltration, and an increase in aqueous protein and TNF-α levels. LAU-0901 treatment resulted in a dose-dependent reduction in inflammation, reflected by reduced total protein levels (up to a 64% reduction). Moreover, hypopyon was prevented, leukocytes were absent in vitreous and aqueous humor, and TNF-α levels were reduced by 91%.. The PAF receptor antagonist LAU-0901 decreases ocular inflammation in a rat model of anterior uveitis in a dose-dependent manner, suggesting that use of this molecule may provide a means to attenuate inflammation onset and offer a future alternative or adjunctive treatment for ocular inflammation. Topics: Animals; Aqueous Humor; Dihydropyridines; Disease Models, Animal; Male; Neuroprotection; Platelet Membrane Glycoproteins; Rats; Rats, Inbred Lew; Receptors, G-Protein-Coupled; Signal Transduction; Tumor Necrosis Factor-alpha; Uveitis | 2018 |
TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation.
Topics: Anemia; Animals; Dihydropyridines; Disease Models, Animal; Enzyme Assays; Enzyme Inhibitors; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Inhibitory Concentration 50; Macaca fascicularis; Mice; Mice, Inbred BALB C; Pyridines; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic | 2018 |
Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines' common metabolite against captopril.
During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines' metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M-2 and captopril on hemodynamic parameters and "ischemic cardiomyopathy" development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6th- 35th day. At 35th day rats' hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance. Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Blood Pressure; Captopril; Cardiomyopathies; Dihydropyridines; Disease Models, Animal; Heart; Heart Rate; Hemodynamics; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley | 2017 |
Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats.
Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1mg/kg, i.p.) was administered 60min prior MCAo. The rats were assessed 24h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120min post-reperfusion to assess vasodilatory property of lercanidipine (0.5mg/kg, i.p.) administered at two different time points: 60min post-MCAo and 15min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5mg/kg, i.p.) was administered 15min, 120min and 240min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24h post-MCAo, effectiveness was evident upto 120min. For sub-acute studies same dose/vehicle was repeated for next 3days and magnetic resonance imaging (MRI) was performed 96h after the last dose. Biochemical markers estimated in rat brain cortex 24h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120min post-reperfusion, but failed to show vasodilatation with 15min post-reperfusion group. Lercanidipine (13.78±2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90±2.44%) investigated 96h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as comp Topics: Animals; Blood Pressure; Brain Infarction; Caspase 3; Caspase 9; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Laser-Doppler Flowmetry; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 2; Motor Activity; Nervous System Diseases; Neuroprotective Agents; Rats; Rats, Wistar | 2017 |
A lack of α1A-adrenergic receptor-mediated antidepressant-like effects of S-(+)-niguldipine and B8805-033 in the forced swim test.
The α1-adrenergic receptors (α1-ARs), which belong to a G protein-coupled receptor family, consist of three highly homologous subtypes known as α1A-ARs, α1B-ARs, and α1D-ARs. Our previous findings suggested that α1A-ARs are an important target for imipramine and electroconvulsive therapy. The current study sought to evaluate whether S-(+)-niguldipine and B8805-033, two selective antagonists of α1A-ARs, can evoke antidepressant-like effects in the forced swim test in rats. Both compounds were administered at three time points (24, 5, and 1 h before testing), and the effects of three doses (2, 5, and 10 mg/kg) of each compound were investigated. S-(+)-Niguldipine produced no antidepressant-like effects other than a 14% reduction in immobility time at the highest dose. Although B8805-033 at a dose of 2 mg/kg did not influence the rats' behavior, higher B8805-033 doses (5 and 10 mg/kg) produced significant reductions in immobility time (approximately 42 and 44% vs. controls, respectively; P<0.01). However, this effect was abolished by the concomitant administration of WAY100135, a serotonin receptor antagonist, suggesting that the observed antidepressant-like effects of B8805-033 are unrelated to α1A-ARs. Nevertheless, given the current dearth of selective α1A-AR agonists, the question of whether this particular subtype could be involved in antidepressant therapy mechanisms remains unresolved. Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antidepressive Agents; Dihydropyridines; Dioxins; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Piperazines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Swimming; Time Factors | 2016 |
Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease.
Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD. Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cell Line, Tumor; Dendritic Spines; Dihydropyridines; Disease Models, Animal; Gene Expression Regulation; Heat-Shock Proteins; Humans; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroblastoma; Neuroprotective Agents; Presenilin-1; tau Proteins | 2016 |
Comparison of anti-anginal effect of cilnidipine with those of nicardipine and nifedipine in the vasopressin-induced angina model of rats.
We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex-mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca Topics: Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Coronary Vasospasm; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Male; Nicardipine; Nifedipine; Rats; Time Factors; Vasoconstriction; Vasodilator Agents; Vasopressins | 2016 |
Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer's disease transgenic female mice.
The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD. Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Anxiety Agents; Blood-Brain Barrier; Calcium; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Female; GABAergic Neurons; Glutamate Decarboxylase; Gyrus Cinguli; Hippocampus; Male; Maze Learning; Memory; Mice; Mice, Transgenic; Neuronal Plasticity; Up-Regulation; Vesicular Inhibitory Amino Acid Transport Proteins | 2016 |
Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock.
Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising. Topics: Animals; Blood Glucose; Blood Pressure; Bradycardia; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Fat Emulsions, Intravenous; Female; Heart Arrest, Induced; Humans; Metabolome; Myocardial Contraction; Nifedipine; Pilot Projects; Shock; Swine; Tachycardia | 2016 |
Benidipine prevents oxidative stress, inflammatory changes and apoptosis related myofibril damage in isoproterenol-induced myocardial infarction in rats.
The effects of benidipine on oxidative stress and myocardial apoptosis were assessed in isoproterenol (ISO)-induced myocardial infarction (MI) in wistar rats.. Animals were pretreated with benidipine (1, 3, 10 μg/kg/day Body weight) intravenously for a period of 28 days. After pretreatment, ISO (85 mg/kg Body weight, subcutaneous) was injected in rats at an interval of 24 h to induce MI. Myocardial oxidative stress, cardiac biomarkers, apoptosis, inflammatory mediators, and ultrastructural architecture of the cardiac tissue were assessed in ISO-induced MI in rats.. Significant variation in the level of TBA, antioxidant enzymes (GSH, CAT, SOD, GPx, GRx, GST) in myocardium, cardiac biomarkers (CK-MB, LDH) in serum, Caspase-3, C-reactive protein (CRP), and alteration in ultrastructural architecture of cardiac tissue confirmed the cardiotoxicity induced by ISO. Pretreatment with benidipine preserved the lipid peroxide and antioxidant enzymes, and furthermore showed maintained levels of myocardial biomarker, CRP and caspase-3. Ultrastructure architecture of cardiac tissue was also found to be well preserved.. The present study suggested cardioprotective effect of benidipine which may possibly be due to its antioxidant activity and antiapoptotic nature. Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Biomarkers; Cytoprotection; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation Mediators; Isoproterenol; Lipid Peroxidation; Male; Myocardial Infarction; Myocardium; Myofibrils; Oxidative Stress; Rats, Wistar; Time Factors | 2015 |
Comparison of the cardioprotective and renoprotective effects of the L/N-type calcium channel blocker, cilnidipine, in adriamycin-treated spontaneously-hypertensive rats.
Cilnidipine is an L/N-type calcium channel blocker (CCB). The effects of cilnidipine on N-type channels give it unique organ-protective properties via the suppression of hyperactivity in the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). In the present study, we compared the effects of cilnidipine and amlodipine (an L-type CCB) on cardiac and renal functions in spontaneously-hypertensive rats injected with adriamycin (ADR). After the weekly administration of ADR for 3 weeks, spontaneously-hypertensive rats were orally administered cilnidipine (20 mg/kg per day), amlodipine (3 mg/kg per day), or vehicle once daily for 4 weeks. A control group received saline rather than ADR, followed by vehicle for 4 weeks. Cilnidipine and amlodipine produced similar reductions in blood pressure after 4 weeks. Cilnidipine ameliorated ADR-induced heart and kidney damage, whereas amlodipine slightly improved cardiac echocardiographic parameters, but did not protect against ADR-induced renal damage. Cilnidipine (but not amlodipine) suppressed the reflex SNS and RAAS hyperactivity caused by their antihypertensive effects. Furthermore, cilnidipine and amlodipine treatment decreased the urinary levels of adrenocortical hormones. The protective effects of cilnidipine against ADR-induced renal and cardiac dysfunction might be associated with its blockade of N-type calcium channels, in addition to its pleiotropic actions, which include the inhibition of the RAAS. Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Doxorubicin; Fibrosis; Heart Diseases; Hypertension; Kidney; Kidney Diseases; Male; Myocardium; Rats, Inbred SHR; Renin-Angiotensin System; Sympathetic Nervous System | 2015 |
Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine.
Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24 h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke. Topics: Animals; Brain; Cerebral Infarction; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Signal Transduction | 2015 |
Comparative evaluation of calcium-sensitizing agents, pimobendan and SCH00013, on the myocardial function of canine pacing-induced model of heart failure.
Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacinginduced heart failure model. Topics: Administration, Oral; Animals; Calcium; Cardiotonic Agents; Dihydropyridines; Dilatation, Pathologic; Disease Models, Animal; Dogs; Echocardiography; Female; Heart Failure; Heart Ventricles; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridazines; Stimulation, Chemical; Systole | 2014 |
Proarrhythmic effects of aldosterone during myocardial ischemia-reperfusion: implication of the sarcolemmal-KATP channels.
To assess the electrophysiological impact of aldosterone during myocardial ischemia-reperfusion.. We used an in vitro model of "border zone" using rabbit right ventricle and standard microelectrodes.. Aldosterone (10 and 100 nmol/L) shortened ischemic action potential [action potential duration at 90% of repolarization (APD90), from 55 ± 3 to 39 ± 1 ms and 36 ± 3 ms, respectively, P < 0.05] and induced resting membrane potential (RMP) hyperpolarization in the nonischemic zone (from -83 ± 1 to -93 ± 7 mV and -94 ± 3 mV, respectively, P < 0.05) and in the ischemic zone during reperfusion (from -81 ± 2 to -88 ± 2 mV and -91 ± 2 mV, respectively, P < 0.05). Bimakalim, an ATP-sensitive potassium (K(ATP)) channel opener, also induced RMP hyperpolarization and APD90 shortening. Aldosterone (10 and 100 nmol/L) increased APD90 dispersion between ischemic and nonischemic zones (from 96 ± 3 to 117 ± 5 ms and 131 ± 6 ms, respectively, P < 0.05) and reperfusion-induced severe premature ventricular contraction occurrence (from 18% to 67% and 75%, respectively, P < 0.05). Adding glibenclamide, a nonspecific K(ATP) antagonist, to aldosterone superfusion abolished these effects different to sodium 5-hydroxydecanoate, a mitochondrial-K(ATP) antagonist.. In this in vitro rabbit model of border zone, aldosterone induced RMP hyperpolarization and decreased ischemic APD90 evoking the modulation of K currents. Glibenclamide prevented these effects different to 5-hydroxydecanoate, suggesting that sarcolemmal-K(ATP) channels may be involved in this context. Topics: Action Potentials; Aldosterone; Animals; Benzopyrans; Dihydropyridines; Disease Models, Animal; Female; Glyburide; Heart Ventricles; In Vitro Techniques; KATP Channels; Male; Myocardial Reperfusion Injury; Perfusion; Rabbits; Sarcolemma | 2014 |
Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats.
An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure. Topics: Age Factors; Animals; Azetidinecarboxylic Acid; Blood Pressure; Brain Injuries; Chemokine CCL2; Collagen Type IV; Dihydropyridines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation; Heart Rate; Imidazoles; Laser-Doppler Flowmetry; Male; Matrix Metalloproteinase 9; Motor Activity; Oxidative Stress; Rats; Rats, Inbred SHR; Stroke; Tetrazoles | 2014 |
Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.
Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure.. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice.. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Heart; Heart Failure; Mice, Knockout; Mice, Transgenic; Nitrendipine; Repressor Proteins; Time Factors; Ventricular Function, Left | 2014 |
Benidipine suppresses in situ proliferation of leukocytes and slows the progression of renal fibrosis in rat kidneys with advanced chronic renal failure.
Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K(+) channels (Kv1.3) in their plasma membranes. In our previous study, the overexpression of these channels in leukocytes was strongly associated with their proliferation in kidneys and the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). Since benidipine, a long-acting 1,4-dihydropyridine Ca(2+) channel blocker, is also highly potent as a Kv1.3 channel inhibitor, it could exert therapeutic efficacy in advanced CRF.. Male Sprague-Dawley rats that underwent 5/6 nephrectomy followed by a 14-week recovery period were used as the model of advanced CRF. Benidipine hydrochloride (5 mg/kg) was started at 8 weeks after nephrectomy and orally administered daily for 6 weeks. The histopathological features of the kidneys were examined in vehicle-treated and benidipine-treated CRF rat kidneys. Cellular proliferation of leukocytes and the cortical expression of proinflammatory cytokines were also examined.. In CRF rat kidneys, Kv1.3 channels began to be overexpressed in leukocytes as early as 8 weeks after nephrectomy. In the cortical interstitium of benidipine-treated CRF rat kidneys, both immunohistochemistry and real-time PCR demonstrated decreased expression of fibrotic markers. Benidipine treatment significantly reduced the number of proliferating leukocytes within the cortical interstitium and decreased the expression of cell cycle markers and proinflammatory cytokines.. This study demonstrated for the first time that benidipine slowed the progression of renal fibrosis in rat kidneys with advanced CRF. Kv1.3 channels overexpressed in leukocytes were thought to be the most likely therapeutic targets of benidipine in decreasing the number of proliferating leukocytes and repressing the production of inflammatory cytokines. Topics: Animals; Blood Urea Nitrogen; Calcium Channel Blockers; Cell Proliferation; Creatinine; Cytokines; Dihydropyridines; Disease Models, Animal; Disease Progression; Fibrosis; Kidney; Kidney Failure, Chronic; Kv1.3 Potassium Channel; Leukocytes; Male; Nephrectomy; Rats; Rats, Sprague-Dawley | 2014 |
Azelnidipine suppresses the progression of aortic aneurysm in wild mice model through anti-inflammatory effects.
Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an inflammation-mediated progression of aneurysmal disease is likely responsible for AA growth and eventual rupture. Unfortunately, there remains no reproducible and durable small animal model of aortic aneurysmal disease, the development of which would enable the investigation of the pathophysiology of this vexing condition. The first aim was to establish a useful wild-type mouse model of AA with low mortality. The second aim was to use this model to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect.. Angiotensin II and β-aminopropionitrile (a lysyl oxidase inhibitor) were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic minipump for 4 weeks to generate a wild-type mouse model of AA. Concurrently, azelnidipine (a calcium channel blocker) or a placebo was administrated orally for 4 weeks. Mice were humanely killed and assessed at the end of the 4 weeks of pharmacologic manipulation.. The combined infusion of angiotensin II and β-aminopropionitrile induced degenerative aneurysm of the thoracic and/or abdominal aorta (11/12; 92%). The majority of aneurysms were located in the distal aortic arch and suprarenal abdominal aorta. Although there was no difference in systolic blood pressure between the control and azelnidipine-treated groups, azelnidipine significantly reduced the incidence of AA (2/11; 18%). Azelnidipine treatment reduced the pathologic findings normally associated with aneurysm formation within the aortic wall. Azelnidipine also reduced the number of macrophage antigen-3 (MAC-3)-positive cells in the periaortic adipose tissue and reduced the gene expression levels of tumor necrosis factor-alpha and matrix metalloproteinase-2 and -9 within the aortic wall.. This study demonstrates that combined treatment with angiotensin II and β-aminopropionitrile induces degenerative AAs in wild-type mice, and azelnidipine prevents aneurysm progression via its anti-inflammatory effect. Topics: Aminopropionitrile; Angiotensin II; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Inflammation Mediators; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Sirtuin 1; Time Factors; Tumor Necrosis Factor-alpha | 2013 |
Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition. Topics: Animals; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 4; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Structure-Activity Relationship | 2013 |
Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.
Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose. Topics: Analgesics; Animals; Azepines; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Half-Life; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Pyrazoles; Rats; Structure-Activity Relationship | 2013 |
Possible hepatoprotective effects of lacidipine in irradiated DOCA-salt hypertensive albino rats.
Calcium channel blockers are increasingly used for the treatment of hypertension. Hypertension is an important risk factor for liver damage and several other circulatory abnormalities. The aim of this study was to determine the effects of lacidipine in a irradiation-induced hepatocellular damage model in Deoxyc Orticosterone Acetate (DOCA)-salt-induced hypertensive model in rats. In this study, animals were divided into five groups as follows: control (Group 1), hypertensive (Group 2), irradiated (Group 3), irradiated and hypertensive (Group 4) and irradiated, hypertensive and lacidipine-treated (Group 5). At the end of the experiment, the livers were removed and its homogenates were biochemically examined. Significant differences were found between values of all groups (p < 0.05). Group 3 and particularly Group 4 showed significant increase in lipid peroxidation and Nitric Oxide (NO) and serum tumor necrosis factor-alpha (TNF-alpha) with a significant reduction in serum level of alanine amine transferase (ALT) enzyme and in superoxide dismutase in red blood cells lysates. Lacidipine-treated group (5) showed a significant reduction in elevated systolic blood pressure together with a great protection of ALT and SOD enzymes from the destructive effects of irradiation and hypertension. Additionally, this CCB reduces hepatic NO and serum TNF-alpha levels that were increased in groups (2,3,4). The present study suggests that lacidipine has some important protective effects on liver of hypertensive irradiated albino rats. Topics: Alanine Transaminase; Animals; Blood Pressure; Desoxycorticosterone Acetate; Dihydropyridines; Disease Models, Animal; Hypertension; Lipid Peroxidation; Liver; Liver Diseases; Nitric Oxide; Random Allocation; Rats; Salts; Superoxide Dismutase; Tumor Necrosis Factor-alpha | 2013 |
Ferric iron uptake into cardiomyocytes of β-thalassemic mice is not through calcium channels.
Iron-overload cardiomyopathy is a major cause of death in thalassemic patients. However, pathways of non-transferrin-bound iron (NTBI) uptake into cardiomyocytes under iron-overload conditions are still controversial. We previously demonstrated that Fe(2+) uptake in thalassemic cardiomyocytes is mainly mediated by T-type calcium channels (TTCCs). However, direct evidence regarding Fe(3+) uptake, the other form of NTBI, in thalassemic cardiomyocytes has never been investigated. Hearts from genetic-altered β-thalassemic mice and adult wild-type (WT) mice were used for cultured ventricular cardiomyocytes. Blockers for L-type calcium channel (LTCC), TTCC, transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake was performed by the acetoxymethyl ester of calcein fluorescence assay. Cellular uptake of Fe(3+) under iron-overload conditions in cultured ventricular myocytes of thalassemic mice was greater than that of WT cells (P < 0.01). The iron chelator, deferoxamine, could prevent Fe(3+) uptake into cultured cardiomyocytes. However, blockers of TfR1, DMT1, LTCC, and TTCC could not prevent Fe(3+) uptake into cardiomyocytes. Our findings indicated that, unlike Fe(2+), Fe(3+) uptake in cultured thalassemic cardiomyocytes is not mainly mediated by TfR1, DMT1, LTCC, and TTCC, suggesting that another alternative pathway could play a major role in Fe(3+) uptake in thalassemic cardiomyocytes. Topics: Animals; Azoles; beta-Thalassemia; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, T-Type; Cation Transport Proteins; Cell Survival; Cells, Cultured; Deferoxamine; Dihydropyridines; Disease Models, Animal; Ferric Compounds; Heart Ventricles; Iron Overload; Isoindoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Nitrophenols; Organophosphorus Compounds; Organoselenium Compounds; Quaternary Ammonium Compounds; Receptors, Transferrin; Verapamil | 2013 |
Cilnidipine regulates glucose metabolism and levels of high-molecular adiponectin in diet-induced obese mice.
The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice. Topics: Adipocytes; Adiponectin; Administration, Oral; Animals; Blood Pressure; Calcium Channel Blockers; Cells, Cultured; Diet, High-Fat; Dihydropyridines; Disease Models, Animal; Glucose; Insulin; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Obesity; Resistin; Tumor Necrosis Factor-alpha | 2013 |
The role of PAF/PAFR signaling in zymosan-induced articular inflammatory hyperalgesia.
Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR(-/-)). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB(4) as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory hyperalgesia. Topics: Animals; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Imidazoles; Immune System Diseases; Inflammation; Joint Diseases; Leukocyte Disorders; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neutrophils; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prostaglandins; Receptors, G-Protein-Coupled; Time Factors; Zymosan | 2013 |
The pharmacological differences in antianginal effects of long-lasting calcium channel blockers: azelnidipine and amlodipine.
We examined antianginal effects of azelnidipine and amlodipine in an arginine vasopressin-induced rat anginal model. Oral administration of azelnidipine or amlodipine produced long lasting inhibition of arginine vasopressin-induced ST-segment depression in electrocardiogram. The degrees of inhibition with azelnidipine at doses of 1 and 3 mg/kg were comparable to those with amlodipine at 3 and 10 mg/kg. Both drugs lowered mean blood pressure in a dose-related manner, whereas only azelnidipine decreased heart rate. Azelnidipine at 3 mg/kg and amlodipine at 10 mg/kg produced a similar decrease in the rate pressure product, an index for cardiac oxygen consumption. Their inhibitory effects on calcium-induced vascular contraction were compared in isolated porcine coronary arteries. Both drugs produced a slow-developing inhibition of calcium-induced contraction. Although their inhibitory effects were similar, the way the both drugs inhibited calcium-induced contraction differed with each other. After removing the drug from bathing solution, the inhibitory effects of azelnidipine were not blunted but were sustained for a long time, which indicates that azelnidipine has high vascular affinity. On the other hand, those of amlodipine were rapidly blunted. These results suggest that the mechanisms underlying antianginal effects of azelnidipine differ from those of amlodipine. The antianginal effect with azelnidipine may be accounted for by its high affinity to the coronary blood vessels and the heart rate slowing effect, both of which are not shared with amlodipine. Topics: Administration, Oral; Amlodipine; Angina Pectoris; Animals; Arginine Vasopressin; Azetidinecarboxylic Acid; Blood Pressure; Calcium; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Male; Myocardium; Oxygen Consumption; Rats; Swine; Time Factors; Vasoconstriction | 2013 |
Involvement of N-type Ca(2+) channels in the fibrotic process of the kidney in rats.
N-type Ca(2+) channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca(2+) channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca(2+) channel blocker) and cilnidipine (a dual L/N-type Ca(2+) channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca(2+) channels was significantly upregulated in UUO kidneys compared with that in contralateral kidneys. There were no significant differences in mean blood pressure among the rats tested. Both amlodipine and cilnidipine significantly attenuated fibrotic changes in UUO kidneys. The antifibrotic effect of cilnidipine was more potent than that of amlodipine. Amlodipine as well as cilnidipine reduced type III collagen deposition, α-smooth muscle actin (α-SMA) expression, and interstitial cell proliferation. In addition, cilnidipine significantly reduced deposition of type I collagen and macrophage infiltration in UUO kidneys. With the use of in vivo bromodeoxyuridine labeling, label-retaining cells (LRCs) were identified as a population of tubular cells that participate in epithelial-mesenchymal transition after UUO. Some LRCs migrated into the interstitium, expressed α-SMA and vimentin, and produced several extracellular matrixes in UUO kidneys. The number of interstitial LRCs was significantly decreased by cilnidipine but not amlodipine. These data suggest that N-type Ca(2+) channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis. Topics: Actins; Amlodipine; Animals; Cadherins; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cell Proliferation; Dihydropyridines; Disease Models, Animal; Epithelial-Mesenchymal Transition; Kidney; Macrophages; Male; Rats; Rats, Wistar; Ureteral Obstruction | 2013 |
Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence.
Oxidative stress plays a critical role in liver fibrogenesis. Reactive oxygen species (ROS) stimulate hepatic stellate cells (HSCs), and ROS-mediated increases in calcium influx further increase ROS production. Azelnidipine is a calcium blocker that has been shown to have antioxidant effects in endothelial cells and cardiomyocytes. Therefore, we evaluated the anti-fibrotic and antioxidative effects of azelnidipine on liver fibrosis.. We used TGF-β1-activated LX-2 cells (a human HSC line) and mouse models of fibrosis induced by treatment with either carbon tetrachloride (CCl(4) ) or thioacetamide (TAA).. Azelnidipine inhibited TGF-β1 and angiotensin II (Ang II)-activated α1(I) collagen mRNA expression in HSCs. Furthermore, TGF-β1- and Ang II-induced oxidative stress and TGF-β1-induced p38 and JNK phosphorylation were reduced in HSCs treated with azelnidipine. Azelnidipine significantly decreased inflammatory cell infiltration, pro-fibrotic gene expressions, HSC activation, lipid peroxidation, oxidative DNA damage and fibrosis in the livers of CCl(4) - or TAA-treated mice. Finally, azelnidipine prevented a decrease in the expression of some antioxidant enzymes and accelerated regression of liver fibrosis in CCl(4) -treated mice.. Azelnidipine inhibited TGF-β1- and Ang II-induced HSC activation in vitro and attenuated CCl(4) - and TAA-induced liver fibrosis, and it accelerated regression of CCl(4) -induced liver fibrosis in mice. The anti-fibrotic mechanism of azelnidipine against CCl(4) -induced liver fibrosis in mice may have been due an increased level of antioxidant defence. As azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti-fibrotic therapy. Topics: Angiotensin II; Animals; Antioxidants; Azetidinecarboxylic Acid; Calcium; Calcium Channel Blockers; Carbon Tetrachloride; Cell Line; Cell Survival; Collagen Type I; Collagen Type I, alpha 1 Chain; Dihydropyridines; Disease Models, Animal; Gene Expression Regulation; Humans; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Reactive Oxygen Species; RNA, Messenger; Thioacetamide; Transforming Growth Factor beta1 | 2012 |
L/N-type calcium channel blocker suppresses reflex aldosterone production induced by antihypertensive action.
The L/N-type calcium channel blocker cilnidipine has been shown to suppress aldosterone production induced by angiotensin II (Ang II) in vitro. In addition, cilnidipine also suppresses the reflex tachycardia induced by its antihypertensive action in vivo. We investigated the effects of cilnidipine on the reflex aldosterone production induced by its antihypertensive action, to identify the differences in the effects of cilnidipine from those of the L-type calcium channel blocker nifedipine. Male SHR/Izm rats were anesthetized by intraperitoneal injection of pentobarbital sodium, and administered an intravenous infusion of saline supplemented or not with Ang II for 30 min. Blood pressure was monitored continuously in the femoral artery. Each of the calcium channel blockers under study was administered intravenously as a bolus through the femoral vein 1 min after the start of the Ang II infusion, and blood samples were collected 30 min after the start of the Ang II infusion. Following administration at nonhypotensive doses, all calcium channel blockers tended to decrease the plasma aldosterone. In particular, cilnidipine significantly suppressed the plasma aldosterone levels. On the other hand, under the condition of Ang II-induced hypertension, administration of a hypotensive dosage of cilnidipine showed no effect on the plasma aldosterone levels, whereas a hypotensive dosage of nifedipine significantly increased the plasma aldosterone levels. Our results suggest that the L/N-type calcium channel blocker cilnidipine reduces the plasma aldosterone level by suppressing the aldosterone production induced by reflex upregulation of the renin-angiotensin-aldosterone system associated with reduction of the blood pressure. Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Down-Regulation; Hypertension; Injections, Intravenous; Male; Nifedipine; Rats; Rats, Inbred SHR; Reflex; Renin-Angiotensin System | 2012 |
Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity.
Dihydropyridine-type calcium channel blockers (CCBs) exert potent antihypertensive effects. The CCB azelnidipine decreases heart rate by suppressing sympathetic nerve activity, which affects afferent and efferent arterioles in the glomeruli. We examined whether azelnidipine can improve progressive glomerular injury in comparison with amlodipine by suppressing renal sympathetic nerve activity in Dahl salt-sensitive rats. Glomerular circulation in Dahl salt-sensitive rats was monitored with a charge-coupled device camera before and after administration of amlodipine (0.5 mg kg(-1), bolus injection) or azelnidipine (0.1 mg kg(-1), bolus injection). Systemic sympathetic nerve activity was also compared by analysis of heart rate variability with a telemetry blood pressure monitoring system after crossover administration of amlodipine (1.0 mg kg(-1) per day) and azelnidipine (3.0 mg kg(-1) per day) for 1 week. To investigate renoprotective effects, rats were treated with amlodipine (1.0 mg kg(-1) per day) or azelnidipine (3.0 mg kg(-1) per day) for 3 weeks with or without renal denervation. The efferent arteriole contracted in response to acute amlodipine but not azelnidipine treatment. The low frequency/high frequency ratio, an index of parasympathetic nerve activity, decreased in response to azelnidipine but not amlodipine treatment. In response to chronic treatment, proteinuria and glomerular injury improved to a greater extent with azelnidipine compared with amlodipine. The renoprotective effects of azelnidipine were diminished by renal denervation. Azelnidipine decreased glomerular damage in Dahl salt-sensitive rats to a greater extent than amlodipine. Azelnidipine appeared to decrease intraglomerular pressure by suppressing sympathetic nerve activity. Topics: Amlodipine; Animals; Arterioles; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Heart Rate; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Inbred Dahl; Sympathectomy; Sympathetic Nervous System | 2012 |
Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice.
Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T- and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg(-1) daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2' deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels. Topics: Aldosterone; Animals; Apoptosis; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Down-Regulation; Hemodynamics; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Oxidative Stress; Ventricular Dysfunction, Left | 2012 |
The protective effects of metyrosine, lacidipine, clonidine, and moxonidine on kidney damage induced by unilateral ureteral obstruction in rats.
To investigate the effects of metyrosine, lacidipine, clonidine, and moxonidine on the renal damage in rats with unilateral ureteral ligation by examining the histological evidence of parenchymal damage and tubular dilatation, as well as biochemical changes indicating cell membrane damage and DNA oxidation.. Thirty-six albino Wistar rats were randomly divided into six equal groups: a healthy (intact) group, a unilateral ureteral ligation (control) group, and four drug treatment groups given metyrosine (50 mg/kg), lacidipine (2 mg/kg), clonidine (0.075 mg/kg), or moxonidine (0.2 mg/kg), respectively, for 10 days. The latter five groups underwent ligation of the left ureter. Ten days after the operation, we removed both kidneys from each rat in the control and drug treatment groups for renal pathological and biochemical [malondialdehyde (MDA), total glutathione, 8-hydroxy-2-deoxyguanine (8-OH-Gua)] examinations. Spectrophotometric assays were used to detect the malondialdehyde and total glutathione levels of the renal tissue. High-performance liquid chromatography was used to measure the 8-hydroxy-2-deoxyguanine levels.. When the drug treatment groups were compared with the control group, the drug treatment groups' total glutathione level was higher and their malondialdehyde level was lower than that of the control group (P < 0.05), especially in the clonidine group (P < 0.0001). The 8-hydroxy-2-deoxyguanine levels of the drug treatment groups, except the lacidipine group, were significantly lower than that of the control group (P < 0.0001). There was no significant difference between the contralateral kidneys of the treatment groups and control group, according to the biochemical results. As revealed via light microscopy, clonidine and moxonidine treatment significantly reduced the tubular and glomerular damage, as well as the tubular dilation. The interstitial inflammation of the kidneys in the lacidipine group was higher than that of the other treatment groups. However, the apoptotic cell count was at a high level in both the lacidipine and metyrosine groups. The increase in the collagen content was most pronounced in the lacidipine and metyrosine groups. An examination of the contralateral kidneys showed no marked pathological findings.. The use of a direct or indirect α2-adrenergic receptor agonist for the temporary treatment of unilateral ureteral obstruction-induced renal damage may be important for preventing renal structural injury. A more advanced study is necessary to determine the mechanisms underlying the protective effects of these drugs with regard to renal damage in ureteral obstruction. Topics: Acute Kidney Injury; alpha-Methyltyrosine; Animals; Biopsy, Needle; Clonidine; Dihydropyridines; Disease Models, Animal; Imidazoles; Immunohistochemistry; Kidney; Male; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Ureteral Obstruction | 2012 |
T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice.
Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe(2+) uptake in thalassemic cardiomyocytes are mainly mediated by T-type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L-type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron-overload condition has not been investigated.. An iron-overload condition was induced in genetically altered β-thalassemic mice and adult wild-type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3 months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1 month with continuous iron feeding.. Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non-transferrin-bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron-overloaded thalassemic mice.. DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron-overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron-overloaded mice. Topics: Animals; Azoles; Base Sequence; beta-Thalassemia; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiovascular System; Deferoxamine; Dihydropyridines; Disease Models, Animal; DNA Primers; Heart Rate; Humans; Iron; Iron Chelating Agents; Iron, Dietary; Isoindoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Nifedipine; Nitrophenols; Organ Size; Organophosphorus Compounds; Organoselenium Compounds; RNA, Messenger; Ventricular Function, Left; Verapamil | 2012 |
Combination therapy of olmesartan and azelnidipine inhibits sympathetic activity associated with reducing oxidative stress in the brain of hypertensive rats.
It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg(-1) day(-1)), CAN/AM (4/2.5 mg kg(-1) day(-1)), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment. Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Hypertension; Imidazoles; Male; Olmesartan Medoxomil; Oxidative Stress; Rats; Rats, Inbred SHR; Tetrazoles | 2012 |
Cisternal sustained release dihydropyridines for subarachnoid hemorrhage.
Nimodipine improved outcome in patients with subarachnoid hemorrhage (SAH) although hypotension limited the dose that could be administered systemically. Subarachnoid delivery of nicardipine or nimodipine may be more efficacious. We tested the efficacy of cisternal application of sustained release nicardipine and nimodipine in SAH in monkeys and dogs, respectively. SAH was created in 13 cynomolgus macaques by placement of autologous blood clot around right middle cerebral, anterior cerebral, and internal carotid arteries. Placebo poly-D,L-lactide coglycolide (PLGA), nicardipine PLGA or mibefradil PLGA was inserted in the clots. Catheter and computed tomography angiography (CTA) were performed at baseline and 7 days later (day 7). Cerebral infarction was assessed on day 7 by magnetic resonance imaging. Six dogs underwent baseline angiography and injection of autologous blood plus PLGA or nimodipine-loaded PLGA microparticles into the cisterna magna. Blood injection was repeated 2 days later and angiography 7 and 14 days later. Animals were euthanized and brains were examined histologically. Cerebrospinal fluid and serum nimodipine concentrations were measured. Nicardipine, but not mibefradil PLGA decreased vasospasm in monkeys (paired t-tests) although there was no significant effect on infarctions see on MRI. In dogs, nimodipine-PLGA produced high local concentrations of nimodipine that were associated with reduced basilar artery vasospasm. No untoward histological effects were observed. There was no reduction in microthrombi in animals treated with nimodipine PLGA compared to placebo PLGA. Site-specific, sustained release formulations of dihydropyridines can deliver high concentrations to the cerebrospinal fluid without causing systemic side effects, and may reduce angiographic vasospasm after SAH. Since nimodipine improves outcome in patients with SAH without necessarily preventing vasospasm, further studies are warranted. Topics: Animals; Delayed-Action Preparations; Dihydropyridines; Disease Models, Animal; Dogs; Female; Macaca fascicularis; Nicardipine; Nimodipine; Placebos; Subarachnoid Hemorrhage; Vasodilator Agents; Vasospasm, Intracranial | 2012 |
Discrepant regulation of QT (QTc) interval duration by calcium channel blockade and angiotensin converting enzyme inhibition in experimental hypertension.
Antihypertensive treatment may reduce prolonged QT duration in hypertension. Generally, the reductions of blood pressure and/or of cardiac mass are believed to be the responsible factors. However, drugs are not equivalent in QT modulation despite similar antihypertensive and antihypertrophic action. We investigated the effect of a calcium channel blocker, lacidipine and an angiotensin-converting enzyme inhibitor, enalapril on QT duration in rats. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with lacidipine (at the dose of 1.5 mg/kg per day for WKY and 3 mg/kg per day for SHR) or enalapril (5 mg/kg per day for WKY and 10 mg/kg per day for SHR) during 8 weeks. Tail-cuff systolic blood pressure (sBP), left ventricular weight (LVW), vascular function of isolated aorta and mesenteric artery and duration of QT (and QTc) interval on Frank electrocardiograms were evaluated. As expected, untreated SHR showed elevated sBP, impaired vascular reactivity, increased LVW and prolonged QT when compared with WKY (p < 0.05). After treatment, both agents markedly improved vascular reactivity and reduced sBP in SHR (p < 0.05). Additionally, enalapril reduced LVW in both hypertensive (by 17%; p < 0.05) and normotensive rats (by 13%; p < 0.05) and, consequently, corrected QT duration in SHR. Interestingly, lacidipine also reduced LVW in SHR (by 9%; p < 0.05), but without influence on prolonged QT. Moreover, lacidipine had no effect on LVW in WKYs but prolonged their QT interval (by 10%; p < 0.05). In conclusion, lacidipine did not reverse a progressive prolongation of QT in SHR, despite sBP lowering and LVW reduction. Thus, the lowering of blood pressure and/or reduction of LVW are not sufficient per se to normalize ventricular repolarization in hypertensive cardiac disease. More likely, modulation of QT prolongation by antihypertensive drugs is a function of their complex action on blood pressure, vascular function, cardiac mass and on reflex neurohumoral activation. Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Enalapril; Heart Ventricles; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY | 2012 |
Role of specific T-type calcium channel blocker R(-) efonidipine in the regulation of renal medullary circulation.
Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-)EFO], on the regulation of renal circulation.. Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-)EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 ± 7.0 and 21.0 ± 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 μg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO(2) + NO(3) excretion and decreased urinary hydrogen peroxide (H(2)O(2)) excretion. Intracellular H(2)O(2) fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 μmol/L, 235 ± 52 units), which was significantly inhibited by pre and coincubation with R(-)EFO. R(-)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 ± 62 units).. These results suggest that TCC blockade with R(-)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region. Topics: Angiotensin II; Animals; Blood Flow Velocity; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Disease Models, Animal; Drug Antagonism; Infusions, Intravenous; Ischemia; Kidney Medulla; Laser-Doppler Flowmetry; NG-Nitroarginine Methyl Ester; Nitrogen Dioxide; Nitrogen Oxides; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Renal Circulation; Vasoconstrictor Agents | 2012 |
Lipoxin A₄ inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma.
Platelet-activating factor (PAF) is a bioactive lipid mediator with strong inflammatory properties. PAF induces the expression and activation of metalloproteinase-9 (MMP-9) in corneal epithelial cells and myofibroblasts, and delays epithelial wound healing in an organ culture system. Lipoxin A(4) (LXA(4)) is a lipid mediator involved in resolution of inflammation and cornea epithelial wound healing. We developed an in vivo mouse model of injury to the anterior stroma that is sustained by PAF and evaluated the action of LXA(4). In this model mice were treated with vehicle, PAF alone and in combination with PAF receptor antagonist LAU-0901 or LXA(4). Mice were euthanized 1, 2 and 7 days after injury and corneas were processed for histology (H&E staining) and immunofluorescence with antibodies for MMP-9, α-smooth muscle actin (α-SMA), fibronectin (FN) and neutrophil. Interleukin 1-α (IL-1α) and keratinocyte-derived chemokine (KC/CXCL1) were assayed by ELISA. Myeloperoxidase (MPO) activity was performed in corneal homogenates. In this in vivo model PAF inhibited epithelial wound healing that was blocked by the PAF receptor antagonist LAU-0901. Treatment with LXA(4) significantly reduced the injured area compared to PAF at 1 and 2 days of treatment. The strong stromal cell infiltration and MPO activity stimulated by PAF was also decreased with LXA(4) treatment. PAF increased MMP-9 and decreased FN expression compared to vehicle treatment and less α-SMA positive cells migrated to the wounded area. The PAF actions were reverted by LXA(4) treatment. The results demonstrated a powerful action of LXA(4) in protecting corneas with injuries that compromise the stroma by decreasing inflammation and increasing wound healing. Topics: Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CXCL1; Corneal Stroma; Dihydropyridines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eye Injuries; Fibronectins; Fluorescent Antibody Technique, Indirect; Interleukin-1alpha; Lipoxins; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Wound Healing | 2012 |
Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats.
Ischemic stroke may initiate a reperfusion injury leading to brain damage cascades where inflammatory mechanisms play a major role. Therefore, the necessity for the novel stroke-protecting agents whose the mechanism of action is focused on their anti-inflammatory potency is still on the agenda for drug designers. Our previous studies demonstrated that cerebrocrast (a 1,4-dihydropyridine derivative) and mildronate (a representative of the aza-butyrobetaine class) possessed considerable anti-inflammatory and neuroprotective properties in different in vitro and in vivo model systems. The present study investigated their stroke-protecting ability in an endothelin-1 (ET-1)-induced ischemic stroke model in rats.. Male Wistar rats were pretreated (for 7 days, per os) with cerebrocrast (0.1 mg/kg), mildronate (100 mg/kg), or their combination, followed by the intracerebral injection of ET-1. Functional and behavioral tests were carried out up to 14 days after the ET-1 injection. Ex vivo, the number of degenerated neurons and the infarction size in the cerebral cortical tissue were assessed histologically.. Cerebrocrast and mildronate effectively normalized ET-1-induced disturbances in neurological status, improved the muscle tone, and decreased the number of degenerated cortical cells. Both drugs also reduced the infarction size, and cerebrocrast showed at least a 2-fold higher activity than mildronate. The combination of both drugs did not cause a more pronounced effect in comparison with the action of drugs administered separately.. The 1,4-dihydropyridine and aza-butyrobetaine structures may serve for the design of novel stroke-protecting agents to prevent severe neurological poststroke consequences. Topics: Animals; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelin-1; Male; Methylhydrazines; Neuroprotective Agents; Rats; Rats, Wistar; Stroke | 2012 |
A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation.
We reported previously that hypertonic saline (HS) treatment can prevent or upregulate the function of polymorphonuclear neutrophils (PMNs) via A2a-type adenosine receptors or A3-type adenosine receptors (A3R), respectively. A3R translocate to the cell surface upon PMN stimulation, and thus, HS promotes PMN responses under conditions of delayed HS treatment. Here we investigated if inhibition of A3R improves the protective effects of HS resuscitation in a mouse sepsis model. We found that HS nearly triples extracellular adenosine concentrations in whole blood and that inhibition of A3R with the selective antagonist MRS-1191 dose dependently improves the inhibitory effect of HS. MRS-1191 at a concentration of 1 nM enhanced the inhibitory effect of HS and reduced stimulatory effects of delayed HS treatment. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that MRS-1191 reduces acute lung injury and PMN accumulation in lung tissue. Whereas delayed HS treatment (4 mL/kg of 7.5% NaCl) of mice 1 h after CLP aggravated PMN accumulation, lung tissue damage, and mortality 24 h after CLP, infusion of MRS-1191 (2 ng/kg body weight) combined with HS reduced these detrimental effects of delayed HS treatment. Our data thus show that A3 receptor antagonists can strengthen the beneficial effects of HS resuscitation by avoiding stimulatory adverse effects that result from delayed HS administration. Topics: Adenosine A3 Receptor Antagonists; Animals; Cell Membrane; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Lung; Male; Mice; Neutrophil Infiltration; Neutrophils; Receptor, Adenosine A3; Resuscitation; Saline Solution, Hypertonic; Sepsis; Time Factors | 2011 |
Cardioprotective effects of an active metabolite of furnidipine in 2 models of isolated heart and on in vivo ischemia–induced and reperfusion-induced arrhythmias in rats.
Dihydropyridines are known not only to have antiarrhythmic effects but also to exert a significant cardiac depressive influence. We previously showed that M-2, an active and final metabolite of furnidipine, had cardioprotective effects without the marked cardiac depression seen with this dihydropyridine. We studied the influence of M-2 infusion (10(-7) M) on hemodynamics during low-flow and regional ischemia in the rat working heart. We examined the protection conferred by M-2 infusion (10(-7) M) against effects of veratridine-induced intracellular calcium overload in the Langendorff heart. Additionally, we performed an in vivo study to explore the effects of oral administration of M-2 at different times and doses, in the ischemia- and reperfusion-induced arrhythmias model. M-2 improved coronary flow during low-flow and regional ischemia while favorably maintaining aortic pressure parameters. M-2 provided outstanding protection against deleterious effects of calcium overloading by significantly preventing rise in left ventricular diastolic pressure and decrease in coronary flow. M-2 reduced mortality and incidence and duration of severe arrhythmias while exhibiting differential influence on blood pressure, which depended on dose and time of administration and could suggest its clinical indication. The results of our entire study establish a beneficial cardioprotective role of M-2, which exhibited pleiotropic effects on the ischemic heart by imparting protection in various ways. This combined with good tolerance, long duration of action, low toxicity, and relatively large therapeutic window makes M-2 a promising candidate as a precursor for a new chemical class of cardioprotective drugs. Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Heart; Male; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley | 2011 |
Platelet-activating factor receptor antagonism targets neuroinflammation in experimental epilepsy.
Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation, participates in physiologic signaling in the brain. However, after seizures, PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility, and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models.. The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle, was administrated each day of kindling or daily during the 4 weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage, and inflammation in the hippocampi of both treated groups.. LAU-0901 limits the progression of kindling and attenuates seizure susceptibility 1 week after the kindling procedure. In addition, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation.. Our results indicate that modulation of PAF overactivity attenuates seizure susceptibility, hippocampal hyperexcitability, and neuroinflammation. Topics: Animals; Cell Death; Cytokines; Dihydropyridines; Dinoprostone; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pyramidal Cells; Rats; Rats, Wistar; Receptors, G-Protein-Coupled | 2011 |
L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate-salt hypertensive rats.
Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-β was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group. Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Collagen; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Sodium Chloride; Transforming Growth Factor beta; Treatment Outcome | 2011 |
The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease.
The motor symptoms of Parkinson's disease (PD) are due to the progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNc). Nothing is known to slow the progression of the disease, making the identification of potential neuroprotective agents of great clinical importance. Previous studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have shown that antagonism of L-type Ca2+ channels protects SNc DA neurons. However, this was not true in a 6-hydroxydopamine (6-OHDA) model. One potential explanation for this discrepancy is that protection in the 6-OHDA model requires greater antagonism of Cav1.3 L-type Ca2+ channels thought to underlie vulnerability and this was not achievable with the low affinity dihydropyridine (DHP) antagonist used. To test this hypothesis, the DHP with the highest affinity for Cav1.3L-type channels-isradipine-was systemically administered and then the DA toxin 6-OHDA injected intrastriatally. Twenty-five days later, neuroprotection and plasma concentration of isradipine were determined. This analysis revealed that isradipine produced a dose-dependent sparing of DA fibers and cell bodies at concentrations achievable in humans, suggesting that isradipine is a potentially viable neuroprotective agent for PD. Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Disease Models, Animal; Isradipine; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinsonian Disorders | 2011 |
The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis.
Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster. Topics: Animals; Antioxidants; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Dopamine; Drosophila melanogaster; Nerve Degeneration; Paraquat; Parkinsonian Disorders; Resveratrol; Stilbenes; Substantia Nigra | 2011 |
Azelnidipine, a new calcium channel blocker, promotes skin wound healing in diabetic rats.
Impaired wound healing in diabetes is associated with decreased nitric oxide (NO) bioavailability in wound tissue. We hypothesized azelnidipine (AZL), a new calcium channel blocker with antioxidant properties, would enhance wound healing in streptozotocin-induced diabetic rats by restoring NO synthesis.. Twelve male rats were taken as non-diabetic group. Twenty four rats were taken and caused to be diabetic by a single streptozotocin injection. Diabetic rats were divided randomly to two groups: control and treatment. Half of non-diabetic and also diabetic rats (in each group of control and treatment) randomly served as excisional-wound model and the other half as nitrite-measurement model. Six weeks after causing diabetes, the excisional wound model underwent dorsal full-thickness excisional wounds (1 × 1 cm). After wound healing completion, full-thickness skin samples (1 × 1 cm) were taken from the wound sites for evaluation of stereological parameters. The nitrite-measurement model (6 wk after causing diabetes) underwent insertion of subcutaneous polyvinyl alcohol sponges in dorsum. The rats were killed 2 wk post-wounding, and wound fluid was analyzed. In the study, after wounding, the treatment groups were gavaged with AZL (3 mg/kg/d) and control and non-diabetic groups with AZL vehicle till euthanasia.. AZL accelerated wound healing rate and also improved wound fluid NO level toward normal value in diabetic rats. Volume density of collagen fibers, numerical density of fibroblasts, and length density of vessels were increased in AZL-treated rats compared with control group.. AZL administration promotes diabetic wound healing by stimulating NO production and enhancing histologic processes central to normal wound healing. Topics: Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Male; Nitric Oxide; Nitrites; Rats; Skin; Streptozocin; Wound Healing | 2011 |
Modulation of subthalamic T-type Ca(2+) channels remedies locomotor deficits in a rat model of Parkinson disease.
An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD. Topics: Animals; Benzimidazoles; Cadmium; Calcium; Calcium Channels, T-Type; Cyclopropanes; Dihydropyridines; Disease Models, Animal; Electrophysiology; Male; Mibefradil; Movement; Naphthalenes; Neurons; Nickel; Nitrophenols; Organophosphorus Compounds; Parkinson Disease; Rats; Rats, Wistar | 2011 |
Experimental analyses of synergistic combinations of antibiotics with a recently recognised antibacterial agent, lacidipine.
The cardiovascular drug lacidipine (Lc) is known to possess antibacterial activity. Further potentiation of action is possible by synergism between Lc and an antibiotic or a non-antibiotic. The minimum inhibitory concentration (MIC) of antibiotics, Lc and other non-antibiotics were detected by the agar dilution technique in different bacteria. Synergism was determined by disc diffusion assay, the fractional inhibitory concentration (FIC) index through checkerboard assessment and, also, the protective capacity of the combination by administering the drugs along with 50 x LD(50) challenge dose of virulent Salmonella typhimurium in animal experiments. Synergism between Lc and penicillin was found to be statistically significant (P Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Dihydropyridines; Disease Models, Animal; Drug Synergism; Gram-Negative Bacteria; Gram-Positive Bacteria; Heart; Humans; Liver; Male; Mice; Microbial Sensitivity Tests; Salmonella Infections, Animal; Spleen; Treatment Outcome | 2010 |
Effects of the AT(1) receptor blocker losartan and the calcium channel blocker benidipine on the accumulation of lipids in the kidney of a rat model of metabolic syndrome.
Unfavorable lipid accumulation may occur in the kidneys in the presence of metabolic syndrome and diabetes. The aim of this study was to investigate whether excess lipids would accumulate in the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of metabolic syndrome. From 34 weeks of age, OLETF rats were treated orally with a calcium channel blocker, benidipine (3 mg kg(-1) per day), or an AT1 receptor blocker, losartan (25 mg kg(-1) per day), for 8 weeks. Blood pressure was slightly but significantly higher in the untreated OLETF rats (149+/-4 mm Hg) than in Long-Evans Tokushima Otsuka (LETO) rats (136+/-2 mm Hg), and both losartan (135+/-3 mm Hg) and benidipine (138+/-3 mm Hg) reduced blood pressure in OLETF rats to a level comparable to that in LETO rats. Tissue content of triglycerides (TG) was greater in OLETF rats than in LETO rats (6.24+/-3.77 and 2.85+/-1.32 microg mg(-1) x tissue, respectively), and both losartan and benidipine reduced these values. Histological analysis showed lipid droplets in tubular cells in which increased dihydroethidium fluorescence was present. Expression of peroxisome proliferator-activated receptor-alpha, PGC-1alpha and uncoupling protein-2 was found to be higher in OLETF rats than in LETO rats; however, the expression of these genes was not altered by treatment with either antihypertensive drug. In contrast, both losartan and benidipine increased the amount of total and phosphorylated forms of AMP kinase and the expression of carnitine palmitoyltransferase-1 (CPT-1). In conclusion, treatment of OLETF rats with losartan and benidipine reduced the tissue content of TG, decreased the production of superoxide and regulated the expression of genes related to fatty acid oxidation such as AMP-activated protein kinase and CPT-1 in the kidneys. Topics: AMP-Activated Protein Kinases; Angiotensin II Type 1 Receptor Blockers; Animals; Calcium Channel Blockers; Carnitine O-Palmitoyltransferase; Cholesterol; Dihydropyridines; Disease Models, Animal; Kidney; Lipid Metabolism; Losartan; Male; Metabolic Syndrome; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Superoxides; Triglycerides | 2010 |
Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic apolipoprotein E-deficient mice.
The endothelium modulates vascular tone by synthesizing and releasing several vasodilating factors, including vasodilator prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In the present study, we examined whether an angiotensin-receptor blocker, a calcium-channel blocker or their combination improved EDHF-mediated responses in diabetic apolipoprotein E-deficient (ApoE(-/-)) mice.. We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE(-/-) mice. The diabetic ApoE(-/-) mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mgxkg(-1)xday(-1)), azelnidipine (AZL, 10 mgxkg(-1)xday(-1)), their combination (OLM + AZL), or hydralazine (HYD 5 mgxkg(-1)xday(-1)) for 5 weeks. In the untreated group, systolic blood pressure was significantly higher and both EDHF-mediated relaxation and endothelium-dependent hyperpolarization were markedly reduced as compared with the control group. Although EDHF-mediated relaxation was not significantly improved in the HYD, OLM and AZL groups, it was significantly improved in the OLM + AZL group, as was also the case with phosphorylation of Akt and endothelial NO synthase (eNOS). In contrast, the endothelium-independent relaxation response to sodium nitroprusside or NS-1619 (a direct opener of K(Ca) channels) was unaltered in any group.. OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE(-/-) mice, in which activation of the endothelial Akt - eNOS pathway may be involved. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apolipoproteins E; Azetidinecarboxylic Acid; Biological Factors; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin; Tetrazoles; Vasodilation | 2010 |
SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes.
Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. In the present study, the role of the toll-like receptor (TLR) signaling pathway was investigated in the mechanism of MDB formation in the DDC-fed mouse model. Microarray analysis data mining, performed on the livers of drug-primed mice refed DDC, showed that TLR2/4 gene expression was significantly up regulated by DDC refeeding. SAMe supplementation prevented this up regulation and prevented the formation of MDBs. qRT-PCR analysis confirmed these results. TLR2/4 activates the adapter protein MyD88. The levels of MyD88 were increased by DDC refeeding. The increase of MyD88 was also prevented by SAMe supplementation. Results showed that MyD88-independent TLR3/4-TRIF-IRF3 pathway was not up regulated in the liver of DDC refed mice. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is the downstream protein recruited by the MyD88/IRAK protein complex, and is involved in the regulation of innate immune responses. Results showed a significant increase in the levels of TRAF-6. TRAF-6 activation leads to activation of NFkB and the mitogen-activated protein kinase (MAPK) cascade. The TRAF-6 increase was ameliorated by SAMe supplementation. These results suggest that DDC induces MDB formation through the TLR2/4 and MyD88-dependent signaling pathway. In conclusion, SAMe blocked the over-expression of TLR2/4, and their downstream signaling components MyD88 and TRAF-6. SAMe prevented the DDC-induced up regulation of the TLR signaling pathways, probably by preventing the up regulation of INF-gamma receptors by DDC feeding. INFgamma stimulates the up regulation of TLR2. The ability of SAMe feeding to prevent TLR signaling up regulation has not been previously described. Topics: Animals; Base Sequence; Dihydropyridines; Disease Models, Animal; DNA Primers; Hepatocytes; Humans; Inclusion Bodies; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C3H; Myeloid Differentiation Factor 88; S-Adenosylmethionine; Signal Transduction; TNF Receptor-Associated Factor 6; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Up-Regulation | 2010 |
SAMe prevents the induction of the immunoproteasome and preserves the 26S proteasome in the DDC-induced MDB mouse model.
Mallory-Denk bodies (MDBs) form in the liver of alcoholic patients. This occurs because of the accumulation and aggregation of ubiquitinated cytokeratins, which hypothetically is due to the ubiquitin-proteasome pathway's (UPP) failure to degrade the cytokeratins. The experimental model of MDB formation was used in which MDBs were induced by refeeding DDC to drug-primed mice. The gene expression and protein levels of LMP2, LMP7 and MECL-1, the catalytic subunits in the immunoproteasome, as well as FAT10, were increased in the liver cells forming MDBs but not in the intervening normal hepatocytes. Chymotrypsin-like activity of the UPP was decreased by DDC refeeding, indicating that a switch from the UPP to the immunoproteasome had occurred at the expense of the 26S proteasome. The failure of the UPP to digest cytokeratins would explain MDB aggregate formation. SAMe prevented the decrease in UPP activity, the increase in LMP2, LMP7, and MECL-1 protein levels and MDB formation induced by DDC. DDC refeeding also induced the TNFalpha and IFNgamma receptors. SAMe prevented the increase in the TNFalpha and IFNgamma receptors, supporting the idea that TNFalpha and IFNgamma were responsible for the up regulation of LMP2, LPM7, and FAT10. These results support the conclusion that MDBs form in FAT10 over-expressing hepatocytes where the up regulation of the immunoproteasome occurs at the expense of the 26S proteasome. Topics: Animals; Base Sequence; Cysteine Endopeptidases; Dihydropyridines; Disease Models, Animal; DNA Primers; Gene Expression; Inclusion Bodies; Keratins; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C3H; Multienzyme Complexes; Proteasome Endopeptidase Complex; S-Adenosylmethionine; Ubiquitin; Ubiquitins | 2010 |
Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte.
Clinical studies have indicated the beneficial effect of an L/N-type calcium channel blocker (CCB), cilnidipine, on the progression of proteinuria in hypertensive patients compared with an L-type CCB, amlodipine. In the present study, we examined the effects of cilnidipine and amlodipine on the renal injury in spontaneously hypertensive rat/ND mcr-cp (SHR/ND) and their underlying mechanism.. SHR/ND were treated with vehicle (nU10), cilnidipine [33 mg/kg per day, orally (p.o.); nU11] or amlodipine (20 mg/kg per day, p.o.; nU9) for 20 weeks. SHR/ND developed proteinuria in an age-dependent manner. Cilnidipine suppressed the proteinuria greater than amlodipine did. The immunohistochemical analysis showed that N-type calcium channel and Wilm's tumor factor, a marker of podocyte, were co-expressed. SHR/ND had significantly greater desmin staining, an indicator of podocyte injury, with lower podocin and nephrin expression in the glomeruli than Wistar-Kyoto rat or SHR. Cilnidipine significantly prevented the increase in desmin staining and restored the glomerular podocin and nephrin expression compared with amlodipine. Cilnidipine also prevented the increase in renal angiotensin II content, the expression and membrane translocation of NADPH oxidase subunits and dihydroethidium staining in SHR/ND. In contrast, amlodipine failed to change these renal parameters.. These data suggest that cilnidipine suppressed the development of proteinuria greater than amlodipine possibly through inhibiting N-type calcium channel-dependent podocyte injury in SHR/ND. Topics: Amlodipine; Animals; Base Sequence; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Disease Models, Animal; DNA Primers; Humans; Kidney; Male; Metabolic Syndrome; Oxidative Stress; Podocytes; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; RNA, Small Interfering; Triglycerides | 2010 |
[Antihypertrophic effect of dihydropyridines calcium channel blockers is dependent on their potential of blocking N-type calcium channel].
To compare the effects of amlodipine, benidipine and nifedipine on myocardial hypertrophy and evaluate the underlying mechanism.. Myocardial hypertrophy model was created by transverse aortic constriction (TAC) in C57 BL/6 mice, and plasma catecholamine concentrations were measured 7 days after surgery to confirm the sympathetic activation. The 3 drugs were administered in TAC mice for 7 days and cardiac hypertrophy was evaluated according to the heart-to-body weight ratio (HW/BW). Effects of those drugs on the protein synthesis stimulated by phenylephrine in cultured neonatal cardiac myocytes were also examined.. HW/BW and plasma concentrations of catecholamine were significantly increased in TAC mice one week after surgery in comparison with to sham-operated mice. One week after TAC, the HW/BW ratio was significantly lower in the amolodipine but not nifedipine-treated group than in the TAC group. Administration of nifedipine via minipump infusion for one week did not decrease HW/BW ratio. Treatment with amlodpine or benidipine, but not nifedipine, decreased the neonatal rat myocyte protein synthesis induced by phenylephrine stimulation.. Antihypertrophic effect of DHEs on myocardium is dependent on their potential of blocking N-type calcium channel, and the underlying mechanism involves the sympathetic inhibition. Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cardiomegaly; Dihydropyridines; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Nifedipine | 2010 |
The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet.
The aims of the present study were to compare the effects of cilnidipine [L-type/N-type calcium channel blocker (CCB)] and amlodipine (L-type CCB) alone or in combination with the angiotensin II receptor blocker (ARB), valsartan, on blood pressure (BP), kidney function in Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet were divided into six groups; control (n = 13), two CCB (cilnidipine or amlodipine) groups at 1 mg/kg/day (n = 10), ARB (valsartan) at 10 mg/kg/day (n = 12), cilnidipine + valsartan (CV, n = 12), and amlodipine + valsartan (AV, n = 12). BPs were lower in the combination therapy groups than in those given either drug alone, but only CV inhibited the increase in urinary albumin excretion (UAE) and lowered the glomerular sclerosis score. In addition, AV elevated plasma renin activity and the angiotensin II concentration, and thus failed to inhibit increases in UAE and to lower glomerular sclerosis score. In conclusion, combination therapy with CCB and ARB decreases BP more effectively than either drug alone. When used in combination with valsartan, cilnidipine is more effective than amlodipine for preventing kidney injury. Topics: Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Glomerulonephritis; Hypertension; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Tetrazoles; Time Factors; Valine; Valsartan | 2010 |
Platelet-activating factor receptor plays a role in lung injury and death caused by Influenza A in mice.
Influenza A virus causes annual epidemics which affect millions of people worldwide. A recent Influenza pandemic brought new awareness over the health impact of the disease. It is thought that a severe inflammatory response against the virus contributes to disease severity and death. Therefore, modulating the effects of inflammatory mediators may represent a new therapy against Influenza infection. Platelet activating factor (PAF) receptor (PAFR) deficient mice were used to evaluate the role of the gene in a model of experimental infection with Influenza A/WSN/33 H1N1 or a reassortant Influenza A H3N1 subtype. The following parameters were evaluated: lethality, cell recruitment to the airways, lung pathology, viral titers and cytokine levels in lungs. The PAFR antagonist PCA4248 was also used after the onset of flu symptoms. Absence or antagonism of PAFR caused significant protection against flu-associated lethality and lung injury. Protection was correlated with decreased neutrophil recruitment, lung edema, vascular permeability and injury. There was no increase of viral load and greater recruitment of NK1.1(+) cells. Antibody responses were similar in WT and PAFR-deficient mice and animals were protected from re-infection. Influenza infection induces the enzyme that synthesizes PAF, lyso-PAF acetyltransferase, an effect linked to activation of TLR7/8. Therefore, it is suggested that PAFR is a disease-associated gene and plays an important role in driving neutrophil influx and lung damage after infection of mice with two subtypes of Influenza A. Further studies should investigate whether targeting PAFR may be useful to reduce lung pathology associated with Influenza A virus infection in humans. Topics: Animals; Apoptosis; Blotting, Western; Chickens; Dihydropyridines; Disease Models, Animal; Inflammation Mediators; Influenza A Virus, H1N1 Subtype; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Toll-Like Receptors; Viral Load | 2010 |
Dose-related shortening of ventricular tachycardia cycle length after administration of the KATP channel opener bimakalim in a 4-day-old chronic infarct anesthetized pig model.
Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K( ATP) channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness. Topics: Action Potentials; Anesthesia, General; Animals; Anti-Arrhythmia Agents; Benzopyrans; Cardiac Pacing, Artificial; Chronic Disease; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Infusions, Intravenous; KATP Channels; Male; Myocardial Infarction; Myocardium; Refractory Period, Electrophysiological; Swine; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation | 2009 |
Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection.
Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In PAFR(-/-) mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar (PAFR(-/-)) or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are disease-modifying agents in experimental dengue infection. Topics: Aedes; Animals; Brain; Cell Line; Cytokines; Dengue; Dengue Virus; Dihydropyridines; Disease Models, Animal; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Viral Load | 2009 |
T-type Ca2+ channel blockade prevents sudden death in mice with heart failure.
Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.. We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.. T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Topics: Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Female; Mibefradil; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Nitrendipine; Nitrophenols; Organophosphorus Compounds; Patch-Clamp Techniques | 2009 |
A novel platelet activating factor receptor antagonist reduces cell infiltration and expression of inflammatory mediators in mice exposed to desiccating conditions after PRK.
To study the contribution of a novel PAF receptor antagonist LAU-0901 in the modulation of the increased inflammatory response in mice exposed to dessicating conditions (DE) after PRK.. Eighty 13-14 week old female Balb/C mice were used. They were divided into two groups: One group was treated with LAU-0901 topical drops. The other group was treated with vehicle. In each group ten mice served as controls and ten were placed in DE. The other twenty mice underwent bilateral PRK and were divided in two additional groups: ten mice remained under normal conditions (NC) and the other ten were exposed to DE. After 1 week all animals underwent in vivo confocal microscopy, immunostaining and western blotting analysis.. Confocal microscopy showed an increased number of reflective structures in the corneal epithelium after PRK and exposure to DE in eyes treated with vehicle as compared to eyes treated with LAU-090). Significant decrease of COX-2 and Arginase I expression and reduced alpha SMA cells was observed after PRK and exposure to DE in eyes treated with LAU-0901.. Exposure of mice to a DE after PRK increases the epithelial turnover rate. PAF is involved in the inflammatory cell infiltration and expression of inflammatory cytokines that follow PRK under DE. Topics: Animals; Cytokines; Dihydropyridines; Disease Models, Animal; Dry Eye Syndromes; Epithelium, Corneal; Female; Inflammation; Mice; Mice, Inbred BALB C; Microscopy, Confocal; Photorefractive Keratectomy; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Treatment Outcome | 2009 |
Lercanidipine reduces matrix metalloproteinase-2 activity and reverses vascular dysfunction in renovascular hypertensive rats.
Increased expression/activity of matrix metalloproteinases (MMPs), especially MMP-2, plays a role in the vascular alterations induced by hypertension, and increased oxidative stress is a major factor activating MMPs. Here, we hypothesized that lercanidipine, a calcium channel blocker, could attenuate the increases in oxidative stress and MMP-2 expression/activity in the two-kidney, one-clip (2K-1C) hypertensive rats. Sham-operated or 2K-1C hypertension rats were treated with lercanidipine 2.5 mg/kg/day (or vehicle) starting three weeks after hypertension was induced. Systolic blood pressure was monitored weekly. After five weeks of treatment, aortic rings were isolated to assess endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall were studied in hematoxylin/eosin sections. Aortic MMP-2 levels were determined by gelatin zymography. Aortic MMP-2/tissue inhibitor of metalloproteinases (TIMP)-2 mRNA levels were determined by quantitative real-time RT-PCR. Plasma thiobarbituric acid reactive substances concentrations were determined using a fluorometric method. Lercanidipine attenuated 2K-1C hypertension (224+/-12 versus 183+/-11 mm Hg in 2K-1C rats and 2K-1C + Lercandipine rats, respectively; P<0.01) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Increased MMP-2 and Pro-MMP-2 levels were found in the aortas of 2K-1C rats (all P<0.05). Lercandipine attenuated 2K-1C-induced increases in MMP-2 by more than 60% and blunted 2K-1C-induced increases in oxidative stress (both P<0.001). While hypertension-induced significant aortic wall hypertrophy and approximately 9-fold increases in the ratio of MMP-2/TIMP-2 mRNA expression (both P<0.05), lercandipine did not affect these changes. These results suggest that lercanidipine produces antihypertensive effects and reverses the endothelial dysfunction associated with 2K-1C hypertension, probably through mechanisms involving antioxidant effects leading to lower MMP-2 activation. Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Enzyme Precursors; Gelatinases; Hypertension, Renovascular; Male; Matrix Metalloproteinase 2; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thiobarbituric Acid Reactive Substances; Vasodilation | 2008 |
Enhanced pulsatile pressure accelerates vascular smooth muscle migration: implications for atherogenesis of hypertension.
Clinical studies have suggested that pulsatile pressure is an independent risk factor for atherosclerosis. However, it is unknown whether enhanced pulsatile pressure per se directly accelerates vascular smooth muscle cell (VSMC) migration, an important process of atherosclerosis.. Using our original Pressure-loading system with a Boyden chamber, we examined the direct effects of variable pressures and pulse rates on migration of rat aortic VSMCs in vitro. High pulse pressure (180/90 mmHg, pulsatile vs. 180 mmHg, static), high mean pressure (180/90 vs. 90/0 mmHg, with the same pulse pressure), wide pulse pressure (190/110 vs. 170/130 mmHg, with the same mean pressure), and high pulse rate (120 vs. 40 per min) significantly accelerated the VSMC migration (1.35, 2.38, 1.38 and 1.27-fold, respectively). The increase in intracellular calcium levels measured by fura-2/AM fluorescence was proportional to the magnitude of pressure loaded. The pressure-promoted VSMC migration was significantly inhibited by a phospholipase-C inhibitor U-73122 or a calmodulin inhibitor W-7. Inositol 1,4,5-trisphosphate receptor blockers 2-aminoethoxydiphenyl borate or xestospongin-C significantly inhibited the VSMC migration, whereas a ryanodine receptor blocker ryanodine had no effects. Furthermore, a calcium channel blocker (CCB), azelnidipine, and an angiotensin type-1 receptor blocker, olmesartan, also significantly inhibited the VSMC migration.. These results provide direct evidence for the pro-atherogenic effects of enhanced pulsatile pressure and also suggest that the anti-atherogenic actions of CCBs and angiotensin type-1 receptor blockers are mediated in part by their direct inhibitory effects on VSMC migration in addition to their anti-hypertensive effects. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Atherosclerosis; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Calcium Signaling; Cell Movement; Cells, Cultured; Dihydropyridines; Disease Models, Animal; Equipment and Supplies; Estrenes; Hypertension; Imidazoles; Inositol 1,4,5-Trisphosphate Receptors; Macrocyclic Compounds; Muscle, Smooth, Vascular; Oxazoles; Pyrrolidinones; Rats; Rats, Wistar; Signal Transduction; Tetrazoles; Type C Phospholipases | 2008 |
Desferrithiocin analogues and nephrotoxicity.
The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties? Topics: Administration, Oral; Animals; Cebus; Dihydropyridines; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Iron; Iron Chelating Agents; Iron Overload; Kidney Diseases; Ligands; Lipids; Male; Molecular Conformation; Rats; Rats, Sprague-Dawley; Stereoisomerism; Thiazoles; Water | 2008 |
In vivo imaging of renal redox status during azelnidipine treatment.
The effect of the calcium channel blocker azelnidipine on the redox status of a murine hypertension model was analyzed and imaged using in vivo low frequency electron paramagnetic resonance (EPR). A murine two kidney-one clip (2K1C) hypertension model was produced by a clipping of the right renal artery. The resulting hypertensive mice were treated with low-dose azelnidipine (1 mg/kg/d), with high-dose azelnidipine (3 mg/kg/d) or without azelnidipine (HT group). An EPR system equipped with a loop-gap resonator and an imaging system was employed. Redox status was evaluated as organ reducing activity measured by means of the decay rate (half-lives) of the spin probe 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (Carbamoyl-PROXYL). Four weeks after clipping the mice demonstrated hypertension as expected. After the additional 2 weeks of azelnidipine treatments, the Carbamoyl-PROXYL half-lives of the Low and High azelnidipine groups measured in the upper abdominal area were significantly shorter than those of the HT group, suggesting improvements in the reducing activity. The blood pressures of the three groups showed no significant differences at this time, and there was no correlation between the renal reducing activity and either blood pressure or serum creatinine values. EPR imaging studies revealed that the improvement in abdominal reducing activity was mainly recognized in the kidney but not in the liver. These results indicate that azelnidipine ameliorates renal redox status through an improvement in reducing activity independent of blood pressure control. Topics: Animals; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Hypertension, Renal; Kidney; Male; Mice; Mice, Inbred ICR; Oxidation-Reduction; Oxidative Stress | 2008 |
Azelnidipine decreases sympathetic nerve activity via antioxidant effect in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats.
The long-acting dihydropyridine calcium channel blocker, azelnidipine, is suggested to inhibit sympathetic nerve activity. We previously demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM) activates sympathetic nerve activity. The aim of the present study was to determine whether oral administration of azelnidipine inhibits sympathetic nerve activity and if so to determine whether the effect is mediated by antioxidant effect in the RVLM. Azelnidipine, hydralazine, or vehicle was orally administered for 28 days to stroke-prone spontaneously hypertensive rats. Reductions in systolic blood pressure were similar in azelnidipine and hydralazine groups. Heart rate was significantly higher in the hydralazine group than in the control, but not altered in the azelnidipine group. Urinary norepinephrine excretion as an indicator of sympathetic nerve activity was significantly lower in the azelnidipine group, whereas it was significantly higher in the hydralazine group than in the control. Levels of thiobarbituric acid-reactive substances and nicotinamide adenine dinucleotide phosphate oxidase activity were significantly lower in the azelnidipine group than in control. Superoxide dismutase activity was significantly increased in the azelnidipine group more than in the control. These results suggest that azelnidipine decreases an indicator of sympathetic nerve activity by antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase in the RVLM of stroke-prone spontaneously hypertensive rats. Topics: Administration, Oral; Animals; Antihypertensive Agents; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Heart Rate; Hydralazine; Hypertension; Male; Medulla Oblongata; NADPH Oxidases; Norepinephrine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Superoxide Dismutase; Sympathetic Nervous System; Thiobarbituric Acid Reactive Substances | 2008 |
Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice.
Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a "vasculoprotective calcium channel blocker". Topics: Animals; Aorta, Thoracic; Atherosclerosis; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Chemokine CCL2; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Macaca fascicularis; Male; Mice; Mice, Knockout; Platelet-Derived Growth Factor; Random Allocation; Tunica Intima | 2008 |
Protective effects of amlodipine and lacidipine on ovariectomy-induced bone loss in rats.
Bone is a dynamic organ system that is directly related to calcium and phosphor metabolism. Imbalance in these two parameters upon aging or menopause leads to osteoporosis. Recently, it was also shown by researchers that high blood pressure in elderly women is statistically associated with decreased bone mineral content at the femoral neck, which may increase the susceptibility to fractures. The aim of our study was to investigate the effects of different doses of amlodipine and lacidipine on ovariectomized rat femurs' calcium and phosphor content. Bone calcium and phosphor concentration was measured by a Wavelength Dispersive Spectrometer. Calcium contents of the rat femurs were significantly lower in the ovariectomized group than in the sham group eight weeks after the operation. Amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats, compared to those of control (ovariectomized) group. Both doses of lacidipine (1 and 3 mg/kg) also effectively increased calcium concentrations (P<0.01) significantly in ovariectomized rats. On the other hand amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats compared with those of the sham group. In conclusion, amlodipine and lacidipine improved the bone loss in an ovariectomy induced osteopenic rat model. Our findings suggest that potent calcium channel blockers such as amlodipine and lacidipine have a beneficial effect on bone metabolism, and an antihypertensive effect. Topics: Amlodipine; Animals; Bone and Bones; Calcium; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Femur; Osteoporosis; Ovariectomy; Phosphorus; Rats; Rats, Wistar; Spectrometry, X-Ray Emission | 2008 |
The role of the new Ca2+ antagonist, CV159, in hepatic I/R injury-the evaluation of hepatic organ reducing activity using in vivo and ex vivo EPR.
We investigated the organ-reducing ability of 1,2-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy) hexyl ester (CV159) that exhibits selective blocking of Ca(2+)/calmodulin and inhibition of Ca(2+) overloading in living organisms (Sprague Dawley rats) using an in vivo and an ex vivo electron paramagnetic imaging technique. Decay rates in CV159-treated rats were significantly higher than those in untreated rats and were almost equal to those in the sham group. Both cytosol and mitochondrial superoxide scavenging activity in CV159-treated rats were significantly higher than those in untreated rats, and cytosol superoxide scavenging activity only was slightly higher than that in the sham group. Faint staining for anti-superoxide dismutase antibody was markedly observed in necrotic lesions in the liver of control group. Alanine aminotransferase level in CV-treated rats were significantly decreased as compared with the levels in untreated rats. Electron microscopy showed a decreased number of damaged mitochondria, whereas mitochondrial damage was significantly reduced in CV-treated animals. We conclude that CV159 retains the organ-reducing activity against radicals in hepatic I/R injury that is mediated by the inhibition of Ca(2+) overloading. Topics: Alanine Transaminase; Animals; Calcium; Calmodulin; Dihydropyridines; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Liver; Male; Mitochondria; Myosin-Light-Chain Kinase; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Survival Rate | 2008 |
Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis.
There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and glutathione-S-transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug-primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes. Topics: Animals; Carcinogens; Cells, Cultured; Dihydropyridines; Disease Models, Animal; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Hepatocytes; Hydroxamic Acids; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C3H; Oligonucleotide Array Sequence Analysis; Precancerous Conditions; Proteins; Ubiquitins; Up-Regulation | 2008 |
Effects of antihypertensive drugs and exercise training on insulin sensitivity in spontaneously hypertensive rats.
We examined the effects of antihypertensive drugs, exercise training, and combinations thereof on insulin sensitivity (IS), and the association between this relation and sympathetic activity, muscle fiber composition, and capillary density in spontaneously hypertensive rats (SHR). Six-week-old male SHR were allocated to 7 groups: a control group (C), and groups treated with azelnidipine (Aze) (a calcium channel blocker), olmesartan (Olm) (an angiotensin II type 1 receptor blocker), exercise training (Exe), and combinations of drugs and exercise training (Aze+Exe, Olm+Exe, and Olm+Aze+Exe). At age 18 weeks, IS and sympathetic activity were evaluated by an euglycemic hyperinsulinemic glucose clamp technique and power spectral analysis of systolic blood pressure, respectively. After the experiments, capillary density and muscle fiber composition in soleus muscle were examined. Aze or Exe alone significantly increased IS associated with a significant reduction in sympathetic activity. Olm alone tended to increase IS with little change in sympathetic activity. Aze, Olm, or Exe significantly increased the capillary density and percentage of insulin-sensitive type I fiber. A combination of Aze and Exe or a combination of Olm and Exe tended to increase IS compared with each drug therapy alone. There were significant correlations between IS and sympathetic activity, capillary density, and the percentage of type I fiber in all the rats. We found that Aze improved IS more substantially compared with Olm in SHR. We also found that Aze, Olm, Exe, and combinations thereof improved IS, probably through the modulation of sympathetic activity or capillarity and muscle fiber type in skeletal muscles. Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Combined Modality Therapy; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Heart Rate; Hypertension; Imidazoles; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Regression Analysis; Sympathetic Nervous System; Tetrazoles | 2008 |
Comparison of the antiatherosclerotic effects of dihydropyridine calcium channel blocker and HMG-CoA reductase inhibitor on hypercholesterolemic rabbits.
The antiatherosclerotic effects of the dihydropyridine-type calcium channel blocker, benidipine hydrochloride (benidipine), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin sodium (pravastatin), were compared in hypercholesterolemic rabbits. Male, New Zealand white rabbits were fed a 0.5% cholesterol diet. Pravastatin (10 mg/kg) or benidipine (10 mg/kg) was orally administered once daily after start of feeding. After 8 weeks of cholesterol feeding, serum cholesterol was increased and endothelial function of thoracic aorta was impaired. Pravastatin prevented elevation of serum cholesterol and aortic tunica intima hyperplasia. Although benidipine had little effect on serum cholesterol, it significantly inhibited aortic tunica intima hyperplasia and impairment of endothelial function. Expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mRNA in aorta of hypercholesterolemic rabbit were higher than those of normal rabbit. Benidipine significantly prevented upregulation of VCAM-1 mRNA expression and showed a tendency to inhibit elevation of LOX-1 mRNA expression. Pravastatin significantly prevented upregulation of both VCAM-1 and LOX-1 mRNA expression. The results demonstrate that pravastatin inhibits increase of serum cholesterol and vascular dysfunction in hypercholesterolemic rabbit. Benidipine is effective in preventing vascular hyperplasia without altering serum cholesterol levels and this may be due to inhibition of expression of VCAM-1. Topics: Animals; Aorta, Thoracic; Atherosclerosis; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperplasia; Male; Pravastatin; Rabbits; RNA, Messenger; Scavenger Receptors, Class E; Time Factors; Tunica Intima; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vasodilation | 2007 |
Effects of calcium channel blocker azelnidipine on experimental abdominal aortic aneurysms.
Azelnidipine has recently been recognized in vascular remodeling. However, the effects of azelnidipine on aneurysmal disease have not yet been studied. The aim of this study was to evaluate whether azelnidipine can inhibit a further expansion of aneurysmal disease.. Experimental abdominal aortic aneurysms (AAAs) were created in a rat model by perfusing elastase. The rats in the first group received no treatment (n=10). In the second group (n=10) azelnidipine (2 mg/kg) was administered to the animals from 3 days before perfusion. The aortic diameter (AD) was measured at the time of initial surgery and death on postoperative day 14. The production of matrix metalloproteinases (MMP)-2 and -9 was analyzed by gelatin zymography.. The aortic diameter was smaller in the azelnidipine group than in the control (7.875+/-1.454 vs 10.745+/-0.551 mm, P<0.01). the active MMP-2 and MMP-9 levels decreased in the azelnidipine group. Hematoxylin-eosin and elastin staining revealed fewer changes in the inflammatory infiltrate and degradation of elastin in the azelnidipine group.. Azelnidipine reduced the expansion of experimental AAAs. Azelnidipine therefore appears to influence the inflammatory oxidative response seen in AAAs while also decreasing the MMP-2 and MMP-9 levels. In addition, azelnidipine inhibited aortic dilatation. Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Wistar | 2007 |
Effect of lercanidipine on kidney microanatomy in Cohen-Rosenthal diabetic hypertensive rats.
The study was undertaken to determine the effect of treatment with the dihydropyridine-type calcium antagonist lercanidipine on the renal vasculature in Cohen-Rosenthal diabetic hypertensive rats, a genetic model of hypertension associated with type 2 diabetes mellitus. Eight animals were given a daily oral dose of 3 mg/kg lercanidipine in drinking water for 8 weeks, and 6 control animals received no treatment. The effects on blood pressure, glucose level, and kidney microanatomy were evaluated. Lercanidipine reduced systolic blood pressure and glucose level. In the control group small arteries and glomerular arterioles exhibited wall thickening and luminal narrowing. Lercanidipine administration prevented the changes in small-sized arteries and glomerular arterioles. The glomerular changes observed in the untreated Cohen-Rosenthal diabetic hypertensive rats were not seen in the lercanidipine-treated animals. Lercanidipine also had beneficial effects on the renal vasculature, suggesting that the compound may be considered for treating hypertension associated with diabetes. Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Kidney; Male; Rats; Renal Artery; Renal Circulation | 2007 |
Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury.
Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A(3) receptor-selective agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 +/- 2.6%, n = 8 mice vs. vehicle-treated 28 +/- 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 +/- 910 U/l, n = 13 vs. vehicle-treated 12,600 +/- 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A(3) receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A(2A) antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A(3) receptor was abrogated in phospholipase C-beta2/beta3 null mice, but the protection mediated by the A(1) or A(2A) receptor remained unaffected in these animals. The adenosine A(3) receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-beta and represents a new target for ameliorating skeletal muscle injury. Topics: Adenosine; Animals; Dihydropyridines; Disease Models, Animal; Hindlimb; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Phenethylamines; Phospholipase C beta; Pyrazoles; Pyrimidines; Receptor, Adenosine A1; Receptor, Adenosine A2A; Receptor, Adenosine A3; Reperfusion Injury; Signal Transduction; Xanthines | 2007 |
Beneficial effects of the dual L- and T-type Ca2+ channel blocker efonidipine on cardiomyopathic hamsters.
The T-type Ca2+ channel (TCC) is activated, and abnormalities of the TCC may be related to the pathogenesis of Ca2+ overload, in cardiomyopathic hamster hearts. The aims of the present study were to investigate the alteration in expression of the TCC and to examine the effects of a dual L-and T-type Ca2+ channel blocker, efonidipine (EFO), on cardiac function and TCC during development of heart failure in UM-X7.1 cardiomyopathic hamsters.. UM-X7.1 and golden hamsters were examined, and EFO was administered at the age of 20 weeks for 4 weeks. Cardiac function was examined, the expression of TCCalpha1G was measured, and ventricular myocytes were subjected to a patch-clamp study. At 24 weeks, vehicle-treated UM-X7.1 hamsters exhibited significant increases in left ventricular (LV) size, with marked decreases in ejection fraction (LVEF) compared with golden hamsters. In the UM-X7.1 group, the expression of TCCalpha1G increased during development of heart failure compared with the golden hamster group. In the UM-X7.1 group, EFO treatment significantly attenuated the decrease of LVEF without affecting blood pressure compared with the vehicle group. EFO treatment decreased heart rate (by approximately 10%) in both groups. In the golden hamster group, EFO treatment did not affect LV function. The TCC current in ventricular myocytes was significantly increased in UM-X7.1, and was inhibited by EFO in a dose-dependent manner.. In cardiomyopathic hamster hearts, abnormalities in the TCC may be at least in part related to the pathogenesis of abnormal Ca2+ homeostasis, and TCC-blocker treatment may decrease the TCC current, resulting in an improvement of cardiac function. TCC blocker therapy might be a new strategy for certain types of heart failure. Topics: Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiomyopathies; Cricetinae; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophysiology; Female; Heart Rate; Male; Mesocricetus; Myocytes, Cardiac; Natriuretic Peptide, Brain; Nitrophenols; Organophosphorus Compounds; Patch-Clamp Techniques | 2007 |
Alkali-induced corneal stromal melting prevention by a novel platelet-activating factor receptor antagonist.
To evaluate the effect of LAU0901 (2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester), a novel platelet-activating factor (PAF) receptor antagonist, on a rabbit model of severe corneal alkali injury.. Adult New Zealand albino rabbits were anesthetized and the right eyes were injured with 2N sodium hydroxide for 60 seconds using a 12-mm plastic well, then rinsed. After the injury, 10 rabbits were treated topically with LAU0901 every 2 hours 4 times per day and received a subconjunctival injection of 200 microL of LAU0901 once per week and 10 rabbits were treated with vehicle the same way. Over the course of 4 weeks, the corneas were examined daily by slitlamp microscopy and corneal ulcers were graded with a clinical scoring system. Ten additional rabbits were treated as described but 1 rabbit from each group was killed at 1, 3, 7, 14, or 21 days after injury. The corneas were processed for histopathologic and immunofluorescence examination.. Persistent epithelial defects were present in both groups from day 5 postinjury, but from day 9 through day 25, the average clinical scores of both epithelial defects and stromal ulcerations in the vehicle-treated eyes were significantly higher than those in the LAU0901-treated eyes (P<.01). By day 28, 90% of the eyes in the vehicle-treated group perforated, while only 20% of the eyes in the LAU0901-treated group developed deep ulceration and none were perforated. Histologic examination showed that the corneas treated with LAU0901 for 4 weeks were completely reepithelialized, with fewer inflammatory polymorphonuclear leukocytes and more repair fibroblasts (myofibroblasts) in the stroma as compared with those treated with vehicle.. LAU0901 inhibits corneal ulceration and perforation in a severe alkali-burn model in the rabbit. In the cornea, PAF is a strong inflammatory mediator, a chemotactic to inflammatory polymorphonuclear leukocytes, and an inducer of several proteases that degrade the extracellular matrix. Clinical Relevance The inhibition of PAF action by LAU0901 could be important in the immediate and intermediate treatment of chemical injuries to preserve the integrity of the cornea. Topics: Animals; Apoptosis; Burns, Chemical; Corneal Stroma; Corneal Ulcer; Dihydropyridines; Disease Models, Animal; Eye Burns; Female; In Situ Nick-End Labeling; Male; Platelet Membrane Glycoproteins; Rabbits; Receptors, G-Protein-Coupled; Rupture, Spontaneous; Sodium Hydroxide | 2006 |
Novel pirfenidone analogues: synthesis of pyridin-2-ones for the treatment of pulmonary fibrosis.
A new series of polysubstituted 1-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their antifibrotic activity. Among the tested compounds, compounds IIc and IVb exhibited higher antifibrotic activity than the standard pirfenidone PD with a reduction of the hydroxyproline level to 50 and 140 micromol/lung, respectively. However, bicyclic pyridone VIIIb displayed a high mortality rate. Detailed syntheses, spectroscopic and biological data are reported. Topics: Administration, Oral; Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Bleomycin; Bronchoalveolar Lavage Fluid; Creatinine; Dihydropyridines; Disease Models, Animal; Hydroxyproline; Intubation, Intratracheal; L-Lactate Dehydrogenase; Lung; Male; Molecular Structure; Pulmonary Fibrosis; Pyridones; Rats; Time Factors; Urea | 2006 |
AVE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat.
The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF.. Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 microg x kg(-1) x min(-1)), the Ca2+ sensitizer EMD57033 (1 mg x kg(-1) x min(-1)), the L-type Ca2+ channel agonist BayY5959 (0.1 mg x kg(-1) x min(-1)), and AVE0118 (0.01 to 0.2 mg x kg(-1) x min(-1)). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to <10%. Digoxin and dobutamine failed to increase atrial contractility. EMD57033 restored 41% and BayY5959 restored 48% of atrial contractility at baseline. BayY5959 significantly prolonged QT duration by 24.7%. AVE0118 enhanced atrial contraction to 156% of the baseline value. The positive inotropic effect was accompanied by a pronounced prolongation of atrial action potential duration and refractoriness, whereas QT duration remained unchanged.. Conventional positive inotropic drugs showed limited effect on atrial contractility after cardioversion of AF or produced QT prolongation. In contrast, the I(to)/I(Kur) blocker AVE0118 fully restored atrial contraction without proarrhythmic effects on the ventricle. Topics: Action Potentials; Animals; Atrial Fibrillation; Atrial Function, Right; Biphenyl Compounds; Cardiotonic Agents; Delayed Rectifier Potassium Channels; Digoxin; Dihydropyridines; Disease Models, Animal; Dobutamine; Electric Countershock; Electrocardiography; Goats; Myocardial Contraction; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Quinolines; Thiadiazines | 2006 |
The calcium-channel blocker, azelnidipine, enhances the inhibitory action of AT1 receptor blockade on ischemic brain damage.
The combined effects of a calcium-channel blocker (CCB) with an angiotensin (Ang) II type 1 (AT1) receptor blocker were investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion.. In male C57BL/6J mice, permanent occlusion of the MCA-induced focal cerebral ischemia and neurological deficit after 24 h, accompanied by a reduction of cerebral blood flow and an increase in superoxide production in the ischemic area. Administration of azelnidipine, a CCB, at 1.0 mg/kg per day for 10 days significantly suppressed these changes after MCA without affecting systolic blood pressure. Such inhibitory effects of azelnidipine on brain ischemia could be observed in AT1a receptor-deficient mice. In addition, olmesartan, an AT1 receptor blocker, at 3.0 mg/kg per day also diminished the ischemic brain area and neurological score, as well as superoxide production and the reduction of cerebral surface blood flow in C57BL/6 mice. The combination of lower doses of azelnidipine (0.1 mg/kg per day) and olmesartan (0.5 mg/kg per day) significantly attenuated the ischemic brain area, neurological score, superoxide production and the reduction of cerebral surface blood flow after MCA occlusion in C57BL/6 mice, whereas either of these agents alone at these doses did not affect brain ischemia.. These results indicate that azelnidipine inhibited ischemic brain damage induced by MCA occlusion, at least in part, through suppression of blood flow change and oxidative stress via a signaling mechanism independent of AT1 receptor stimulation. Moreover, azelnidipine synergistically enhanced the inhibitory action of olmesartan on brain ischemia, suggesting beneficial combined effects of a CCB with an AT1 receptor blocker on ischemic brain damage. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Azetidinecarboxylic Acid; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Imidazoles; Male; Mice; Mice, Inbred C57BL; Tetrazoles | 2006 |
Anti-arrhythmic and cardio-protective effects of furnidipine in a rat model: a dose response study.
Protective effects of acute oral or intravenous doses of furnidipine against ischemia and re-perfusion-induced arrhythmias and creatine kinase release were studied in a rat model for cardiac ischemia and re-perfusion. Transient cardiac ischemia was induced by occluding the left coronary descending artery of anaesthetized rats for 7 min, and re-perfusion period studied was 15 min. Pre-treatment period for oral doses (1, 5 or 10 mg/kg) was 1 h, whereas that for the intravenous ones (1.25, 2.5, 5 or 10 microg/kg) was 10 min. After both routes of administration, significant protective effects of furnidipine on creatine kinase release were observed after the two lowest doses only. In contrast, its higher dosages were more effective in preventing re-perfusion-induced mortality, arrhythmias and hypotensive episodes, and for transiently lowering arterial blood pressure before initiation of ischemia. These observations suggest potential uses of furnidipine for preventing re-perfusion triggered lethal arrhythmias. Efforts to evaluate therapeutic potential of low dose furnidipine as a cardio-protective agent seem warrantable. Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Ventricles; Injections, Intravenous; Male; Myocardial Reperfusion Injury; Protective Agents; Rats; Rats, Sprague-Dawley; Survival Rate | 2006 |
Effects of benidipine in a rat model for experimental angina.
To compare the antianginal effects of 1,4-dihydropyridine-type calcium-channel blockers, we evaluated the effects of benidipine, amlodipine, nifedipine, and efonidipine on vasopressin-induced myocardial ischemia in rats, an experimental model of angina. Intravenous administration of benidipine (3 microg/kg), amlodipine (1000 microg/kg), and nifedipine (100 microg/kg) suppressed the vasopressin-induced S-wave depression, an index of myocardial ischemia. Efonidipine (100 microg/kg, i.v.) tended to inhibit the S-wave depression. At the antianginal dose of each drug, amlodipine, nifedipine, and efonidipine decreased blood pressure significantly, whereas benidipine had little effect on blood pressure at a dose of 3 microg/kg. These results indicate that benidipine, unlike the other 1,4-dihydropyridine-type calcium-channel blockers examined in this study, inhibits vasopressin-induced coronary vasospasm with fewer undesirable effects such as hypotension in rats, suggesting that benidipine may be useful in the treatment of angina pectoris. Topics: Amlodipine; Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Male; Nifedipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred Strains | 2006 |
SCH00013, a novel Ca(2+) sensitizer with positive inotropic and no chronotropic action in heart failure.
We investigated the effects of the agent SCH00013 on Ca(2+)-induced force generation in rabbit skinned cardiac muscle fibers and in vivo cardiac function in high-pacing-induced heart failure dogs. The Ca(2+)-induced force generation in skinned cardiac muscle fibers was determined at pH 6.2 - 7.4, and SCH00013 was found to have a significant Ca(2+) sensitizing effect at pH 7.2 to 7.4. There was no significant difference in the Ca(2+) sensitizing action between the enantiomers of SCH00013. The Ca(2+) sensitizing effect of SCH00013 was dependent on the sarcomere length, being significant only at a long sarcomere length. SCH00013 elicited a positive inotropic effect at more than 0.3 and 1 mg/kg, i.v. in normal and heart failure dogs, respectively, with no chronotropic action. These results strongly suggested that SCH00013 is a novel Ca(2+) sensitizer that elicits a positive inotropic and no chronotropic effect in heart failure, probably through enhancing the Frank-Starling mechanism. Topics: Amrinone; Animals; Calcium; Cardiotonic Agents; Dihydropyridines; Disease Models, Animal; Dogs; Heart Failure; Heart Rate; Hydrogen-Ion Concentration; Injections, Intravenous; Male; Myocardial Contraction; Myocytes, Cardiac; Pyridazines; Rabbits; Sarcomeres; Stereoisomerism; Ventricular Function, Left | 2005 |
Emergence of a R-type Ca2+ channel (CaV 2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage.
Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death on thousands of individuals each year. In addition to vasospasm in large diameter arteries, enhanced constriction of resistance arteries within the cerebral vasculature may contribute to decreased cerebral blood flow and the development of delayed neurological deficits after SAH. In this study, we provide novel evidence that SAH leads to enhanced Ca2+ entry in myocytes of small diameter cerebral arteries through the emergence of R-type voltage-dependent Ca2+ channels (VDCCs) encoded by the gene CaV 2.3. Using in vitro diameter measurements and patch clamp electrophysiology, we have found that L-type VDCC antagonists abolish cerebral artery constriction and block VDCC currents in cerebral artery myocytes from healthy animals. However, 5 days after the intracisternal injection of blood into rabbits to mimic SAH, cerebral artery constriction and VDCC currents were enhanced and partially resistant to L-type VDCC blockers. Further, SNX-482, a blocker of R-type Ca2+ channels, reduced constriction and membrane currents in cerebral arteries from SAH animals, but was without effect on cerebral arteries of healthy animals. Consistent with our biophysical and functional data, cerebral arteries from healthy animals were found to express only L-type VDCCs (CaV 1.2), whereas after SAH, cerebral arteries were found to express both CaV 1.2 and CaV 2.3. We propose that R-type VDCCs may contribute to enhanced cerebral artery constriction after SAH and may represent a novel therapeutic target in the treatment of neurological deficits after SAH. Topics: Animals; Blood; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, R-Type; Cerebral Arteries; Cisterna Magna; Dihydropyridines; Diltiazem; Disease Models, Animal; Drug Resistance; Injections; Ion Transport; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nifedipine; omega-Agatoxin IVA; omega-Conotoxin GVIA; Patch-Clamp Techniques; Rabbits; Spider Venoms; Subarachnoid Hemorrhage; Vasoconstriction; Vasospasm, Intracranial | 2005 |
Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats.
The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent. Topics: Angina Pectoris; Animals; Dihydropyridines; Disease Models, Animal; Male; Methacholine Chloride; Rats; Rats, Sprague-Dawley; Vasodilator Agents; Vasopressins | 2005 |
The N- and L-type calcium channel blocker cilnidipine suppresses renal injury in dahl rats fed a high-sucrose diet, an experimental model of metabolic syndrome.
The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine.. Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation.. Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group.. Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action. Topics: Amlodipine; Animals; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dietary Sucrose; Dihydropyridines; Disease Models, Animal; Hypertension, Renal; Kidney Diseases; Male; Metabolic Syndrome; Rats; Rats, Inbred Dahl; Treatment Outcome | 2005 |
Ammodendrine and N-methylammodendrine enantiomers: isolation, optical rotation, and toxicity.
Ammodendrine (1) was found to occur as a mixture of enantiomers in two different collections of plants identified as Lupinus formosus. The ammodendrine fraction was reacted in a peptide coupling reaction with 9-fluorenylmethoxycarbonyl-L-alanine (Fmoc-L-Ala-OH) to give diastereomers, which were separated by preparative HPLC. The pure D- and L-ammodendrine enantiomers were then obtained by Edman degradation. Optical rotation measurements revealed that the D- and L-enantiomers had optical rotations of [alpha]24D +5.4 and -5.7, respectively. D- and L-N-methylammodendrine enantiomers were synthesized from the corresponding ammodendrine enantiomers, and their optical rotations established as [alpha]23D +62.4 and -59.0, respectively. A mouse bioassay was used to determine the difference in toxicity between these two pairs of naturally occurring enantiomers. The LD50 of (+)-D-ammodendrine in mice was determined to be 94.1 +/- 7 mg/kg and that of (-)-L-ammodendrine as 115.0 +/- 7 mg/kg. The LD50 of (+)-D-N-methylammodendrine in mice was estimated to be 56.3 mg/kg, while that of (-)-L-N-methylammodendrine was determined to be 63.4 +/- 5 mg/kg. These results establish the rotation values for pure ammodendrine and N-methylammodendrine and indicate that there is little difference in acute murine toxicity between the respective enantiomers. Topics: Animals; Cattle; Cattle Diseases; Chromatography, High Pressure Liquid; Dihydropyridines; Disease Models, Animal; Lupinus; Mice; Molecular Structure; Piperidines; Plants, Edible; Pyridines; Stereoisomerism | 2005 |
Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice.
Angiotensin II type 1 receptor blockers (ARB) are widely recognized to have a vasculoprotective effect. Accumulating data have revealed that calcium antagonists also retard atherosclerosis. We examined the possibility that combination therapy of ARB and calcium antagonists could more effectively prevent atherosclerosis than monotherapy.. We observed a marked increase in the atherosclerotic area, associated with the exaggerated expression of nicotinamide adenine dinucleotide (phosphate), reduced form [NAD(P)H] oxidase subunits (p22 and p47) and superoxide anion production, in the aorta of apolipoprotein E-deficient mice maintained on a 1.25% high-cholesterol diet for 10 weeks. A calcium antagonist, azelnidipine, at a dose of 1 mg/kg a day or an ARB, olmesartan, at a dose of 3 mg/kg a day, significantly inhibited these parameters, with no change in systolic blood pressure and the blood cholesterol level. Moreover, the co-administration of lower doses of azelnidipine (0.1 mg/kg a day) and olmesartan (1 mg/kg a day) significantly inhibited the atherosclerotic area and oxidative stress, whereas azelnidipine or olmesartan alone at these doses did not affect these parameters. Furthermore, we observed similar inhibitory effects of azelnidipine or olmesartan on angiotensin II-induced NADPH oxidase activity and Akt activity in cultured vascular smooth muscle cells.. These results suggest that the co-administration of calcium antagonists and ARB synergistically blunts oxidative stress at least partly through the inhibition of Akt activity and enhances the beneficial effects of these drugs on atherosclerosis compared with monotherapy. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apolipoproteins E; Arteriosclerosis; Azetidinecarboxylic Acid; Blotting, Western; Calcium Channel Blockers; Cells, Cultured; Dihydropyridines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Imidazoles; Mice; Mice, Knockout; Muscle, Smooth, Vascular; NADPH Oxidases; Olmesartan Medoxomil; Oxidative Stress; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Superoxides; Tetrazoles; Time Factors | 2005 |
Cilnidipine, an N+L-type dihydropyridine Ca channel blocker, suppresses the occurrence of ischemia/reperfusion arrhythmia in a rabbit model of myocardial infarction.
Dihydropyridine Ca channel blockers are widely prescribed for the treatment of hypertension and coronary artery diseases, but it remains unknown whether these agents protect against arrhythmias. We investigated whether cilnidipine, an N+L-type Ca channel blocker, reduces the incidences of ventricular premature beats (VPBs) and, if so, via what mechanisms. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Cilnidipine (0.5 or 1.0 microg/kg/min, i.v.) or saline (i.v.) was administered from 30 min before ischemia to 30 min after reperfusion. Electrocardiogram and blood pressure were monitored and the incidences of VPBs were measured. At 48 h after reperfusion, myocardial infarct was measured. Myocardial interstitial noradrenaline levels were determined before, during and after 30 min of ischemia with cilnidipine (0.5 and 1.0 microg/kg/min) or saline. The incidences of VPBs during ischemia and reperfusion were significantly attenuated in the cilnidipine 0.5 group (15.6 +/- 3.1 and 6.8 +/- 1.9 beats/30 min) and in the cilnidipine 1.0 group (10.4 +/- 4.9 and 3.5 +/- 1.0 beats/30 min) compared to the control group (27.2 +/- 4.5 and 24.2 +/- 3.1 beats/30 min), respectively. Myocardial interstitial noradrenaline levels were significantly reduced in the cilnidipine 0.5 and 1.0 groups compared to the control group during ischemia and reperfusion. The antiarrhythmic effect of cilnidipine may be related to the attenuation of cardiac sympathetic nerve activity. This finding may provide new insight into therapeutic strategies for hypertensive patients with ventricular arrhythmias. Topics: Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Heart Rate; Incidence; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Norepinephrine; Rabbits; Survival Rate; Sympathetic Nervous System; Tachycardia, Ventricular; Ventricular Fibrillation; Ventricular Premature Complexes | 2005 |
Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning.
Ischemic preconditioning (IPC) elicits two distinct windows of cardioprotection, an early phase that lasts for 1-2 h and a delayed phase that lasts for 24-72 h. However, there is conflicting data as to how long the heart is resistant to IPC-induced cardioprotection after the initial protection wanes, leading to the demonstration of IPC-resistance. This resistance to IPC appears to be dependent on the timing of the next IPC stimulus, the species of animals used and the model studied. Furthermore, the mechanisms responsible IPC-resistance are unknown. It is also important to demonstrate therapeutic interventions that will produce cardioprotection during this period of IPC-resistance.. To examine potential mechanisms responsible for acute IPC-induced resistance, the NHE-1 inhibitor EMD 85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoylguanidine), which exerts its effects via mechanisms distinct from IPC, and the K(ATP) channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open K(ATP) channels, were examined in a canine model of IPC-resistance. One 10 min. IPC stimulus followed by 10 min. of reperfusion produced a significant reduction in IS/AAR compared to Control (7.1 +/- 2.6% versus 26.0 +/- 6.2%; P < 0.05). However, IPC did not significantly protect the myocardium if a 2 h reperfusion period occurred between the initial IPC stimulus and the subsequent prolonged (60 min) ischemic challenge (IS/AAR: 22.5 +/- 4.8%: P > 0.05). Furthermore, hearts treated with IPC followed by 2 h of reperfusion were resistant to an additional IPC stimulus administered just prior to the subsequent 60 min. occlusion period (IS/AAR: 22.9 +/- 3.2%: P > 0.05). In contrast, administration of the NHE-1 inhibitor EMD 85131 (IS/AAR: 7.4 +/- 2.5%: P < 0.05) or the K(ATP) channel opener bimakalim (IS/AAR: 11.8 +/- 2.4%: P < 0.05) both afforded significant cardioprotection when administered at 2 h of reperfusion in previously preconditioned canine hearts resistant to IPC.. IPC resistance occurs in this canine model of ischemia-reperfusion injury. However, in spite of IPC resistance, hearts can still be pharmacologically protected by direct application of the K(ATP) channel opener bimakalim or the NHE inhibitor EMD 85131. Topics: Animals; Benzamides; Benzopyrans; Cardiotonic Agents; Dihydropyridines; Disease Models, Animal; Dogs; Heart; Ischemic Preconditioning, Myocardial; Myocardial Infarction; Potassium Channels; Pyrroles; Reperfusion Injury; Sodium-Hydrogen Exchangers; Time Factors | 2005 |
Prevention of experimental diffuse lamellar keratitis using a novel platelet-activating factor receptor antagonist.
To determine whether a novel platelet-activating factor (PAF) antagonist prevents experimentally induced diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK).. Department of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, Louisiana, USA.. Twenty eyes of 10 New Zealand albino rabbits were used. The left eyes were treated with a peribulbar injection of 0.5 mL of PAF receptor antagonist LAU 0901 (2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester) dissolved in 20 hydroxypropyl B cyclodextrin (30 microg /mL). Two rabbits were treated with a peribulbar injection of 0.5 mL of vehicle (cyclodextrin) alone and served as controls. A corneal flap was cut in all eyes, and the interface was exposed to Pseudomonas aeruginosa endotoxin. The left eyes were additionally treated with 1 drop of LAU 0901 4 times a day. Rabbits were killed on postoperative days 1, 2, 3, 5, and 8. The eyes were enucleated and processed for histopathology and immunohistochemical examination.. Corneas not treated with LAU 0901 and controls showed a severe inflammatory response in the flap margin and stromal interface, characterized by loss of keratocytes, activation of adjacent keratocytes and transformation to myofibroblasts, infiltration of polymorphonuclear leukocytes and monocytes, and presence of epithelial cells with necrosis and melting of adjacent stroma. Corneas of rabbits treated with LAU 0901 showed minimal loss of keratocytes and myofibroblast transformation, minimal inflammatory cell infiltration, and minimal presence of epithelial cells in the interface.. Induction of DLK was blocked by a PAF receptor antagonist in rabbit eyes. The histopathological evaluation and immunohistochemical studies showed that treatment with LAU 0901 blocked keratocyte apoptosis, transformation of fibroblasts to myofibroblasts and migration to the wound site, and chemotaxis of inflammatory cells, inhibiting the inflammatory response and promoting adequate healing of the flap interface and adjacent stroma. Topics: Actins; Animals; Apoptosis; Cell Differentiation; Cell Movement; Cells, Cultured; Chondroitin Sulfates; Cornea; Dihydropyridines; Disease Models, Animal; Endotoxins; Fibroblasts; Fluorescent Antibody Technique, Indirect; Immunoenzyme Techniques; In Situ Nick-End Labeling; Keratitis; Ophthalmic Solutions; Platelet Membrane Glycoproteins; Pseudomonas; Rabbits; Receptors, G-Protein-Coupled | 2004 |
Role of manidipine in the management of patients with hypertension.
Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers. Topics: Adult; Aged; Animals; Biological Availability; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Male; Maximum Tolerated Dose; Middle Aged; Nitrobenzenes; Piperazines; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome | 2004 |
The calcium channel antagonist benidipine reduces plasma and cardiac endothelin-1 levels in type II diabetic rat model.
Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications. Topics: Age Factors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Disease Models, Animal; Down-Regulation; Endothelin-1; Insulin Resistance; Male; Myocardium; Rats; Rats, Inbred OLETF; Rats, Long-Evans | 2004 |
Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3).
Multidrug resistance has been a major problem in cancer chemotherapy. In this study, in vitro and in vivo modulations of MDR by ginsenoside Rg(3), a red ginseng saponin, were investigated. In flow cytometric analysis using rhodamine 123 as an artificial substrate, Rg(3) promoted accumulation of rhodamine 123 in drug-resistant KBV20C cells in a dose-dependent manner, but it had no effect on parental KB cells. Additionally Rg(3) inhibited [3H]vinblastine efflux and reversed MDR to doxorubicin, COL, VCR, and VP-16 in KBV20C cells. Reverse transcriptase-polymerase chain reaction and immuno-blot analysis after exposure of KBV20C cells to Rg(3) showed that inhibition of drug efflux by Rg(3) was due to neither repression of MDR1 gene expression nor Pgp level. Photo-affinity labeling study with [3H]azidopine, however, revealed that Rg(3) competed with [3H]azidopine for binding to the Pgp demonstrating that Rg(3) competed with anticancer drug for binding to Pgp thereby blocking drug efflux. Furthermore, Rg(3) increased life span in mice implanted with DOX-resistant murine leukemia P388 cells in vivo and inhibited body weight increase significantly. Topics: Affinity Labels; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Biological Transport; Dihydropyridines; Disease Models, Animal; Drug Resistance, Multiple; Fluorescent Dyes; Ginsenosides; Humans; KB Cells; Leukemia P388; Mice; Rhodamine 123; Tritium; Tumor Cells, Cultured; Vinblastine | 2003 |
Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model.
Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents. Topics: Acetic Acid; Animals; Colitis; Dihydropyridines; Disease Models, Animal; Drug Interactions; Intestinal Mucosa; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Thiazoles | 2003 |
Role of PAF receptors during intestinal ischemia and reperfusion injury. A comparative study between PAF receptor-deficient mice and PAF receptor antagonist treatment.
1 The reperfusion of ischemic tissues may be associated with local and systemic inflammation that prevents the full benefit of blood flow restoration. The present study aimed to confirm a role for platelet-activating factor receptor(s) (PAFR) during ischemia and reperfusion injury by using genetically modified mice deficient in the PAFR (PAFR(-/-) mice) and to evaluate comparatively the effectiveness of pharmacological treatment using the PAFR antagonist UK-74,505 (modipafant). 2 The reperfusion of the ischemic superior mesenteric artery (SMA) induced marked local (intestine) and remote (lungs) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx and intestinal hemorrhage and in the production of TNF-alpha. There was also a systemic inflammatory response, as shown by the increase in serum TNF-alpha concentrations and marked reperfusion-associated lethality. 3 After reperfusion of the ischemic SMA, PAFR(-/-) mice had little tissue or systemic inflammation and lethality was delayed, but not prevented, in these mice. Interestingly, the reperfusion-associated increases in tissue concentrations of IL-10 were significantly greater in PAFR(-/-) than wild-type mice. 4 Pretreatment with PAFR antagonist UK-74,505 (1 mg kg(-1)) markedly prevented tissue injury, as assessed by the increase in vascular permeability, neutrophil accumulation, hemorrhage and TNF-alpha concentrations in the intestine and lungs. In contrast, UK-74,505 failed to affect reperfusion-associated lethality and increases in serum TNF-alpha when used at 1 mg kg(-1). 5 Reperfusion-associated lethality and increase in serum TNF-alpha were only affected when a supra-maximal dose of the antagonist was used (10 mg kg(-1)). At this dose, UK-74,505 also induced a marked enhancement of reperfusion-associated increases in tissue concentrations of IL-10. However, at the same dose, UK-74,505 failed to prevent reperfusion-associated lethality in PAFR(-/-) mice any further. 6 The present studies using genetically modified animals and a receptor antagonist firmly establish a role of PAFR activation for the local, remote and systemic inflammatory injury and lethality which follows reperfusion of the ischemic SMA in mice. Moreover, it is suggested that high doses of PAFR antagonists need to be used if the real efficacy of these compounds is to be tested clinically. Topics: Animals; Dihydropyridines; Disease Models, Animal; Imidazoles; Intestinal Diseases; Intestines; Lung Diseases; Male; Mesenteric Artery, Superior; Mice; Mice, Inbred C57BL; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Reperfusion Injury | 2003 |
Cardiotonic agent SCH00013 prolongs survival of cardiomyopathic hamsters.
The authors examined the effects of long-term treatment with SCH00013, a novel cardiotonic agent with calcium-sensitizing action, on survival of hereditary cardiomyopathic BIO 14.6 hamsters. Sixty-nine male hamsters at 223 days of age were divided into untreated, SCH00013-low (approximately 1 mg/kg/d), and SCH00013-high (approximately 10 mg/kg/d) groups. Survival curves were constructed in the three groups. The first deaths in the untreated, SCH00013-low, and SCH00013-high groups were found at 263, 290, and 314 days of age, respectively. A 50% mortality rate was observed at 392 days in the untreated group, 396 days in the SCH00013-low group, and 445 days in SCH00013-high group. The survival time distribution of the SCH00013-high group was significantly different from that of the untreated group (P < 0.005). However, histomorphometric examinations revealed that the degree of progression of calcification and fibrosis in the ventricular wall of the BIO 14.6 hamsters was not different between the untreated and SCH00013-treated groups. Plasma concentration of this agent was 2 microM at the end of the second week of continuous administration via drinking water in SCH00013-high group. Thus, SCH00013 was beneficial for the survival of cardiomyopathic hamsters, suggesting that this agent is a possible candidate for the treatment of chronic heart failure. Topics: Animals; Cardiomyopathies; Cardiotonic Agents; Cricetinae; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Myocardial Infarction; Pyridazines; Survival Rate | 2003 |
Glucose-lowering in a db/db mouse model by dihydropyridine diacid glycogen phosphorylase inhibitors.
The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model. Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Enzyme Inhibitors; Glycogen Phosphorylase; Hypoglycemic Agents; Mice | 2003 |
Cilnidipine improves spontaneously hypertensive rat coronary hemodynamics without altering cardiovascular mass and collagen.
The present study was designed to determine the effects of prolonged treatment with cilnidipine, a novel dihydropyridine calcium antagonist which blocks both L-type and N-type calcium channels, on systemic, regional and coronary hemodynamics, cardiovascular mass and collagen content in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats.. Male 23-week-old WKY and SHR rats were divided into two groups for each strain. One group received cilnidipine (10 mg/kg per day), whereas their respective controls were given no therapy. Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic mass, and hydroxyproline concentration were determined after 12 weeks treatment.. The data demonstrated that cilnidipine neither affected systemic hemodynamics nor cardiovascular mass and collagen content in WKY rats. The same treatment in the SHR reduced arterial pressure and total peripheral resistance without changes in heart rate and cardiac index. Ventricular and aortic mass indices as well as ventricular collagen content remained unchanged. There were no differences in organ blood flows between two SHR groups, whereas renal, liver and left ventricular coronary vascular resistances were reduced by cilnidipine. After dipyridamole infusion left ventricular minimal coronary vascular resistance decreased further in cilnidipine-treated SHR as compared with control SHR rats.. These data suggest that cilnidipine, an L- and N- type calcium channel antagonist, exerted beneficial effects on coronary hemodynamics without altering cardiovascular mass or collagen content in SHR. Topics: Animals; Calcium Channel Blockers; Cardiovascular System; Collagen; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Male; Models, Cardiovascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Ventricular Function | 2002 |
Lacidipine inhibits adhesion molecule and oxidase expression independent of blood pressure reduction in angiotensin-induced vascular injury.
Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-kappaB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II--dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-kappaB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-kappaB activation. Topics: Angiotensins; Animals; Blood Pressure; Cell Adhesion Molecules; Dihydropyridines; Disease Models, Animal; Oxidoreductases; Rats; Rats, Sprague-Dawley; Vascular Diseases | 2002 |
Long-acting calcium channel blocker benidipine suppresses expression of angiogenic growth factors and prevents cardiac remodelling in a Type II diabetic rat model.
Calcium channel blockers, widely used for the treatment of hypertension and angina, could prevent cardiovascular complications in patients with diabetes. They can improve cardiac remodelling in animal models of a variety of cardiovascular diseases. Here, we examined the therapeutic effect of benidipine, a long-acting calcium channel blocker, on cardiac remodelling in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model.. The methods for morphometric analysis included double staining for coronary capillaries, dye-binding staining for collagen content and Masson's trichrome staining for perivascular fibrosis. Immunohistochemical and in situ hybridization techniques were used for detecting protein and mRNA expressions for vascular endothelial growth factors (VEGF), basic fibroblast growth factors (bFGF) and TGF-beta(1), endothelial nitric oxide synthase (eNOS), and anti- and pro-apoptotic markers.. OLETF rats showed an increased coronary capillary density, a reduced venular capillary proportion, an increased cardiac collagen content and prominent cardiac perivascular fibrosis. In OLETF rat hearts, significant increases in vascular expressions for VEGF, bFGF and TGF- beta(1) were found. Furthermore, the apoptosis signalling pathways, involving eNOS and apoptotic markers, were markedly altered, and coronary endothelial cell apoptosis was lower. These alterations with the exception of eNOS expression were significantly blocked by benidipine treatment.. The suppressive effect of benidipine on overproduction of angiogenic growth factors could prevent cardiac angiogenesis and fibrosis, resulting in an improvement of cardiac remodelling in diabetes. As VEGF and bFGF potently block endothelial cell apoptosis execution, physiological apoptosis revived by benidipine treatment could also contribute to coronary vessel regression. Topics: Animals; Calcium Channel Blockers; Capillaries; Collagen; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dihydropyridines; Disease Models, Animal; Endothelial Growth Factors; Fibroblast Growth Factor 2; Gene Expression Regulation; Lymphokines; Male; Neovascularization, Pathologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Inbred Strains; RNA, Messenger; Species Specificity; Transcription, Genetic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors | 2002 |
Anti-inflammatory effects of cerebrocrast in a model of rat paw edema and on mononuclear THP-1 cells.
Cerebrocrast (IOS 1.1212; 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di(2-propoxyethyl) diester) is a novel derivative of 1,4-dihydropyridine, which does not antagonize Ca(2+) influx in neuronal tissues. Since several classical dihydropyridines possess anti-inflammatory properties, we first studied the effects of cerebrocrast in a model of rat paw edema induced by carrageenan. Cerebrocrast had a preventative effect in this model of inflammation, with maximal activity (32-45% inhibition) in the 0.1-0.25 mg kg(-1) range. It was ineffective when added after the injection of carrageenan. Subsequent in vitro experiments showed that cerebrocrast in the micromolar range inhibited secretion of interleukin-1 beta, interleukin-6 and neurotoxic products by cells of the human monocytic THP-1 line while failing to affect secretion of tumor necrosis factor (TNF-alpha). It also lacked any direct neuroprotective effect against toxic secretions from stimulated THP-1 cells. The data obtained suggest that cerebrocrast may be useful not only in various inflammatory disorders of peripheral tissues, but also in treating neurodegenerative diseases, where inflammatory mechanisms in general and microglial activation, in particular, are thought to play an important role. Topics: Animals; Anti-Inflammatory Agents; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Forelimb; Humans; Male; Monocytes; Rats; Rats, Wistar; Tumor Cells, Cultured | 2002 |
NC-1500 prevents concanavalin A-induced mice hepatitis without affecting cytokine gene expression.
NC-1500 is a dihydropyridine type calcium channel blocker. The effect of NC-1500 on mice concanavalin A-induced hepatitis was examined. Treatment of mice with concanavalin A (Con A) caused elevation of plasma transaminase. Pretreatment of mice with NC-1500 (3, 10 and 30 mg/kg, p.o.) prevented this Con A-induced elevation of plasma transaminase. Treatment of mice with Con A induced tumor necrosis factor-alpha (TNF-alpha) mRNA expression in the liver. However, NC-1500 (30 mg/kg, p.o.) did not affect this Con A-induced TNF-alpha mRNA expression in the liver. The present results showed that NC-1500 inhibited Con A-induced hepatitis without affecting TNF-alpha mRNA expression in the liver. Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Calcium Channel Blockers; Chemical and Drug Induced Liver Injury; Concanavalin A; Dihydropyridines; Disease Models, Animal; Female; Gene Expression; Glycyrrhizic Acid; Mice; Mice, Inbred BALB C; Naphthyridines; RNA, Messenger; Tumor Necrosis Factor-alpha | 2001 |
Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol-fed hamsters.
We have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins; these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 +/- 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells; lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity. Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Calcium Channel Blockers; Cholesterol; Cholesterol, Dietary; Cricetinae; Dihydropyridines; Disease Models, Animal; Lipids; Lipoproteins; Male; Mesocricetus | 2000 |
Effects of benidipine hydrochloride on cerebrovascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats: evaluation by magnetic resonance imaging.
We determined possible protective effects of benidipine hydrochloride (benidipine), a dihydropyridine calcium antagonist, on cerebrovascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). The animals were orally treated with benidipine at 1, 3 and 10 mg/kg daily for 7 weeks, and their neurological symptoms, body weight changes, systolic blood pressure and cerebrovascular lesions on magnetic resonance imaging (MRI) were determined at various time points of treatment. Moreover, the brains of the rats that showed cerebrovascular lesions on MRI in the course of treatment or completed 7-week treatment were examined histopathologically. Control rats presented such symptoms as sedation, ataxia and aggressiveness, while their MRI analysis revealed high signals over wide areas from the occipital to frontal cortex and from the corpus callosum to external capsule. These high signal areas corresponded in location to edematous or softening lesions revealed by the histopathological observation. Treatment with benidipine at 3 and 10 mg/kg ameliorated neurological symptoms, significantly suppressing cerebrovascular damages on MRI. Benidipine at 3 mg/kg significantly decreased blood pressure for the first four weeks but it did not thereafter. These findings demonstrate that benidipine can protect salt-loaded SHRSP from cerebrovascular injury as assessed by MRI. Topics: Analysis of Variance; Animals; Blood Pressure; Body Weight; Brain; Cerebrovascular Disorders; Dihydropyridines; Disease Models, Animal; Magnetic Resonance Imaging; Male; Psychomotor Performance; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary; Vasodilator Agents | 2000 |
Benidipine, a long-acting calcium-channel blocker, prevents the progression to end-stage renal failure in a rat mesangioproliferative glomerulonephritis.
Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.. This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.. Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.. These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA. Topics: Actins; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Disease Models, Animal; Disease Progression; Fluorescent Antibody Technique; Glomerulonephritis, Membranoproliferative; Hydralazine; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Transforming Growth Factor beta; Vasodilator Agents | 2000 |
Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat.
The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF-alpha levels. Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg(-1)) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg(-1)) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-alpha levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-alpha. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-alpha. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans. Topics: Animals; Azepines; Capillary Permeability; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Intestine, Small; Male; Mesenteric Artery, Superior; Neutrophils; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Polysaccharides; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Reperfusion Injury; Triazoles; Tumor Necrosis Factor-alpha | 2000 |
Effects of pranidipine, a calcium channel antagonist, in an avian model of heart failure.
We have previously demonstrated that turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) develop dilated cardiomyopathy (DCM) which approximates the human condition [1-3]. We wanted to study the effects of a calcium channel blocker in an animal model with a documented decrease in beta-receptor density, increased levels of circulating catecholamines, and abnormal calcium metabolism. The effects of a third generation calcium channel blocker has not been studied in our model. We hypothesized that the model would be predictive of the human condition and provide additional insights into the potential use of Ca2+ channel blockers in the setting of DCM. In the present study, we examined the effect of pranidipine, a new dihydropyridine calcium antagonist, in the setting of DCM on the gross and microscopic morphology of the heart and the overall contractile performance of the myocardium. A state of symptomatic to mild cardiomyopathy was induced in Broad-Breasted White turkey poults by administration of Fz for three weeks. Blood pressure, heart rate, fractional shortening, and body weight were monitored and compared in DCM animals treated with pranidipine and those given a placebo. After four weeks of treatment or no treatment with pranidipine, animals were euthanized and heart weight, cardiac dimensions, and microscopic morphology were compared. Progressive left ventricular (LV) dilatation and wall thinning was prevented with pranidipine treatment. In addition, microscopic examination demonstrated myocyte hypertrophy regression in DCM animals treated with pranidipine. In DCM animals, treatment with pranidipine resulted in significantly smaller left ventricular dimensions. We conclude that the calcium channel blocker pranidipine was not detrimental to global cardiac function in animals with dilated cardiomyopathy. Topics: Animals; Anti-Infective Agents, Local; Calcium; Calcium Channel Blockers; Cardiomyopathy, Dilated; Dihydropyridines; Disease Models, Animal; Furazolidone; Hemodynamics; Myocardial Contraction; Organ Size; Turkeys | 1999 |
Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene overexpression after aortic banding.
Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy. Topics: Actins; Animals; Antihypertensive Agents; Aortic Diseases; Blood Pressure; Carbazoles; Carotid Arteries; Carvedilol; Constriction, Pathologic; Dihydropyridines; Disease Models, Animal; Endothelin-1; Endothelins; Gene Expression; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Labetalol; Ligation; Male; Myocardium; Organ Size; Propanolamines; Protein Precursors; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger | 1999 |
Platelet-activating factor plays a pivotal role in the induction of experimental lung injury.
We have previously described a model of acute lung injury in the mouse in which intravenous administration of lipopolysaccharide (LPS) results in a marked sequestration of neutrophils in the pulmonary microvasculature, although this by itself was not sufficient to induce injury. If the sequestered neutrophils were exposed to zymosan, then a striking increase in pulmonary vascular permeability to albumin was found, suggesting that sequestered neutrophils may produce one or more mediators capable of acting directly on the capillary endothelium. Because activated neutrophils are known to release platelet-activating factor (PAF), we hypothesized that PAF produced locally within the pulmonary capillaries may be the mediator involved. Treatment of mice with the PAF antagonist UK-74,505 prior to administration of zymosan alone or combined LPS and zymosan resulted in a substantial attenuation of lung injury, as measured by the accumulation of extravascular 125I-labeled human serum albumin. UK-74,505 had no effect on neutrophil sequestration as measured by myeloperoxidase activity in whole lung tissue and as assessed by light microscopy. Administration of UK-74,505 after LPS, but before zymosan, was also effective at inhibiting lung injury but again, neutrophil sequestration was unaffected. In contrast, UK-74,505 had no effect on cobra venom factor-induced lung injury and neutrophil sequestration. These data suggest that PAF production is involved in the increases in pulmonary vascular permeability, but not in the sequestration of neutrophils, induced by zymosan alone or by combined LPS and zymosan treatment. Early treatment with PAF antagonists may be beneficial in preventing the development of acute lung injury in humans. Topics: Animals; Capillary Permeability; Dihydropyridines; Disease Models, Animal; Elapid Venoms; Extravascular Lung Water; Female; Humans; Imidazoles; Lipopolysaccharides; Lung; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Respiratory Distress Syndrome; Serum Albumin; Skin; Zymosan | 1998 |
Catalepsy induced by calcium channel blockers in mice.
It is known that calcium channel blockers induce Parkinsonism. In this study, amlodipine-, diltiazem-, and verapamil-induced catalepsy was investigated in mice. All of these three calcium channel blockers induced catalepsy. Dopamine D1, D2, and mACh receptor occupancies were estimated under the same conditions, and the affinities of these drugs for each receptor were also estimated in vitro. Intensity of catalepsy was predicted by dopamine D1, D2, and mACh receptor occupancies with the dynamic model which had already been constructed and was compared with the observed values. The predicted and the observed values were comparable (r = 0.98, p < 0.001). In conclusion, the dynamic model considering D1, and D2, and mACh receptor occupancy may be useful for quantitative prediction of drug-induced catalepsy. Topics: Amlodipine; Animals; Binding, Competitive; Calcium Channel Blockers; Catalepsy; Dihydropyridines; Diltiazem; Disease Models, Animal; Flunarizine; Male; Mice; Muscarinic Antagonists; Nitrobenzenes; Piperazines; Predictive Value of Tests; Receptors, Cholinergic; Receptors, Dopamine D1; Receptors, Dopamine D2; Scopolamine; Time Factors; Verapamil | 1998 |
Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.
Functional and structural changes of chronic renal allograft failure share similarities with other chronic nephropathies with low nephron number. In models of reduced nephron number, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prevented proteinuria and retarded renal lesions. This study investigates whether blockade of angiotensin II activity prevented chronic allograft injury in the Fisher 344 --> Lewis rat kidney transplant model, and compares its effect with that of calcium channel blockers, the main antihypertensive agents used in transplant patients to control BP. Transplanted rats received either no treatment (control), the type 1 angiotensin II receptor antagonist losartan, or the calcium channel blocker lacidipine. Rats received cyclosporine for the first 10 d posttransplant to prevent acute rejection. Doses of antihypertensive drugs were adjusted to achieve a comparable level of BP control throughout the study. Awake systolic BP was comparable in animals given losartan or lacidipine during the 6-mo observation period. Daily treatment with losartan but not lacidipine resulted in a significant decrease in the amount of proteinuria, preserved glomerular and tubulointerstitial structure, and improved graft survival compared with corresponding parameters in control untreated rats. GFR, measured as inulin and p-aminohippurate clearances, respectively, in rats surviving the 6-mo follow-up, was numerically but not significantly higher in losartan-treated animals than in all other groups. Thus, at comparable levels of BP control, losartan but not lacidipine effectively protects animals from chronic allograft injury and allows long-term survival. Topics: Analysis of Variance; Animals; Calcium Channel Blockers; Chronic Disease; Dihydropyridines; Disease Models, Animal; Graft Rejection; Kidney; Kidney Function Tests; Kidney Transplantation; Losartan; Male; Nephrotic Syndrome; Rats; Rats, Inbred F344; Rats, Inbred Lew; Reference Values; Survival Rate; Transplantation, Homologous | 1998 |
Effect of lercanidipine and its (R)-enantiomer on atherosclerotic lesions induced in hypercholesterolemic rabbits.
The in vivo antiatherogenic activity of the calcium antagonist lercanidipine and its (R)-enantiomer was investigated in two different types of atherosclerotic lesions (hyperplastic and fatty-streak lesions) in rabbits. Lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) as well as its (R)-enantiomer at 3 mg kg(-1) week(-1) were given by subcutaneous injection for 10 weeks to White New Zealand rabbits, with cholesterol feeding beginning at week 2. The hyperplastic lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty streak lesions were induced by cholesterol feeding. In untreated animals (n=5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries without collar showed a intima/media (I/M) ratio of 0.03+/-0.02, whereas in carotids with a collar the ratio was 2+/-0.42. In lercanidipine-treated animals a significant and dose-dependent effect on intimal hyperplasia was observed. I/M ratios were 0.73+/-0.4, 0.42+/-0.1, 0.32+/-0.1 for 0.3, 1, and 3 mg kg(-1) week(-1), respectively (P<0.05). The lercanidipine enantiomer (3 mg kg(-1) week(-1)) was as effective as the racemate (0.41+/-0.11). Proliferation of smooth muscle cells, assessed by incorporation of BrdU into DNA, was reduced by about 50%, 70%, 85%, and 80% by lercanidipine (0.3, 1, and 3 mg kg(-1) week(-1)) and its (R)-enantiomer, respectively. The area of fatty-streaks in the aorta (n = 11-15) was significantly reduced by lercanidipine (3 mg kg(-1) week(-1), 16% vs 27%, P<0.05), a trend was observed also with lower doses. When different segments of the aorta were considered (arch, thoracic, abdominal) a significant and dose-dependent effect in the thoracic and abdominal aorta was observed also at lower doses. The (R)-enantiomer was as effective as lercanidipine. These results suggest a direct antiatherosclerotic effect of lercanidipine, independent of modulation of risk factors such as hypercholesterolemia and/or hypertension as demonstrated by the absence of stereoselectivity. Topics: Animals; Arteries; Arteriosclerosis; Calcium Channel Blockers; Cholesterol, Dietary; Dihydropyridines; Disease Models, Animal; Hypercholesterolemia; Hyperplasia; Macrophages; Male; Rabbits | 1998 |
Influence of isradipine, niguldipine and dantrolene on the anticonvulsive action of conventional antiepileptics in mice.
We report the effects of two new dihydropyridine derivatives, isradipine (4-(4'-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-[(5-[p-nitrophenyl]furfurylidene)-amino]hydantoin sodium, an inhibitor of Ca2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5-20 mg/kg), isradipine (5-10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10-20 mg/kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5-5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5-5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4- [(2-trifluoromethyl)-phenyl]-pyridine-5-carboxylate, an L-type Ca2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable. Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Carbamazepine; Dantrolene; Dihydropyridines; Disease Models, Animal; Drug Interactions; Electroshock; Epilepsy; Female; Isradipine; Lethal Dose 50; Mice; Motor Activity; Phenobarbital; Phenytoin; Random Allocation; Seizures; Valproic Acid | 1997 |
Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy.
Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.. To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.. Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.. In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function. Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Calcium-Transporting ATPases; Captopril; Cardiomyopathy, Hypertrophic; Diastole; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Mice; Mice, Transgenic; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Tetrazoles | 1997 |
Effects of long-term treatment with the calcium antagonist AE0047 on cerebrovascular autoregulation and hypertrophy in spontaneously hypertensive rats.
Chronic hypertension is associated with structural and functional changes in the cerebrovascular bed, which influence cerebral circulation and its autoregulation. We examined whether or not long-term treatment of spontaneously hypertensive rats (SHRs) with the new calcium antagonist AE0047 would reverse structural changes in the cerebral vasculature and normalize the elevated lower blood pressure (BP) limit of the cerebral blood flow (CBF) autoregulation. Treating 6-month-old SHRs with a diet containing either 0.013 or 0.04% AE0047 for 8 weeks reduced BP and, at the higher dose, maintained BP at a level similar to that of age-matched Wistar-Kyoto (WKY) rats. At the end of the treatment period, CBF was measured by using the hydrogen-clearance method, and the lower limit of the autoregulation curve was estimated by repeated CBF measurement with stepwise reduction of BP through bleeding. This limit was significantly higher in untreated SHRs than in WKY rats (111 +/- 8 vs. 60 +/- 8 mm Hg). AE0047 caused a significant and dose-dependent shift in the elevated lower BP limit, which decreased to 83 +/- 9 and 75 +/- 6 mm Hg at the low and high dose, respectively. In perfusion-fixed proximal, intermediate, and distal portions of the middle cerebral artery, media thickness/external diameter (M/ED) ratios were significantly greater in untreated SHRs than in WKY rats. In AE0047-treated animals, M/ED ratios in all portions tended to be reduced halfway between those for untreated SHRs and those for WKY rats, but with no statistical significance. These results suggest that long-term treatment of patients with hypertension with AE0047 will normalize the autoregulatory threshold while preserving CBF and thereby improve tolerance to BP reduction, but the potential to ameliorate structural alterations may be small. Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebral Arteries; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Homeostasis; Hypertension; Hypertrophy; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY | 1997 |
Effects of a calcium antagonist, lacidipine, on experimental focal cerebral ischemia in rats.
We investigated the effects of lacidipine on focal cerebral ischemia in rats, and these effects were compared with those of nicardipine. Drugs were administered orally 5 min after middle cerebral artery occlusion (MCAO). Neurological scores as described by Bederson et al. (Stroke 17, 472-476, 1986) and cerebral infarct size (CIS) determined by the 2,3,5-triphenyltetrazolium chloride staining method were measured 24 hr after MCAO. Cerebral blood flow (CBF) and energy metabolites were determined by the hydrogen clearance method and an enzymatic method, respectively. In the drug-untreated group, we observed low-CBF of approximate 13 ml/100 g/min during 0.5-6 hr of occlusion and extensive cerebral infarction associated with severe neurologic deficits (ND). Lacidipine at 1 and 3 mg/kg, although it lowered blood pressure, improved low-CBF to approximate 20 ml/100 g/min during 1.5-6 hr of occlusion and increased tissue levels of ATP 6 hr after MCAO in a dose-dependent manner. Nicardipine at 30 mg/kg also improved low-CBF and increased tissue levels of ATP significantly. However, the improvement of low-CBF by nicardipine was transient. Lacidipine at 3 mg/kg reduced CIS and ameliorated ND significantly. In contrast, nicardipine at 30 mg/kg could not ameliorate ND in spite of a significant reduction of CIS similar to that of lacidipine (3 mg/kg). These results suggest that the improvement of focal cerebral ischemia by lacidipine may be partly due to long-lasting improvement of collateral blood supply to the ischemic area. Topics: Adenosine Triphosphate; Animals; Brain; Calcium Channel Blockers; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Ischemic Attack, Transient; Male; Neurologic Examination; Nicardipine; Rats; Rats, Sprague-Dawley | 1997 |
Calcium channel blockers-induced gingival hyperplasia.
Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Dogs; Female; Gingival Hyperplasia; Humans; Male; Testosterone | 1996 |
[Effects of lacidipine, a new dihydropyridipine derivative, on various cerebral ischemia models].
We examined the cerebral protective effects of lacidipine (L) using three different types of cerebral ischemia models, and the effects were compared with those of nicardipine (N). (1) In the transient forebrain ischemia model of the rat, oral administration of L (0.3 and 1 mg/kg) before ischemia significantly decreased the number of acidophilic neurons in CA1 regions of the hippocampus 7 days after ischemia. N (3 mg/kg, p.o.) before ischemia also produced a significant reduction in the number of acidophilic neurons, and it's effectiveness was almost the same as that of L (1 mg/kg). (2) In the focal cerebral ischemia model of the rat, oral administration of L (1 and 3 mg/kg) before of after left middle cerebral artery occlusion (MCAO) significantly reduced infarct size at 24 hr after MCAO. Such an ameliorative effect was also observed when N was administered orally. However, the effect of N at 30 mg/kg was less than that of L at 1 mg/kg. (3) In the delayed cerebral vasospasm model of the dog after subarachnoid hemorrhage (SAH), intravertebral artery injection of L (10 micrograms/kg) or N (10 micrograms/kg) dilated the contracted basilar artery 3 days after SAH to the level before SAH. Finally, while both L and N increased cerebral blood flow (CBF) in a dose-dependent manner in conscious normal rat, the increment of CBF induced by L at a given level of reduced-blood pressure was greater than that induced by N. These results indicate that lacidipine may be a potential therapeutic agent that exerts a protective effect against brain damage after cerebral ischemia. Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dogs; Ischemic Attack, Transient; Male; Nicardipine; Rats; Rats, Sprague-Dawley | 1996 |
Effects of tetrandrine on left ventricle hypertrophy in deoxycorticosterone acetate-salt hypertensive rats.
The effect of regression of left ventricular hypertrophy was studied in deoxycorticosterone-acetate-salt hypertensive rats (DOCA-salt hypertensive rats) treated with tetrandrine. Treatment with tetrandrine (by gastric intubation, 50 mg/kg per day for 9 weeks) lowered systolic blood pressure, left ventricular weight, Ca2+ of mitochondria, and markedly decreased the density (Bmax) and total number of dihydropyridine binding sites in hypertrophic left ventricle (P < 0.001). There was no difference between groups in dissociation constant (Kd) values of dihydropyridine binding sites. These facts indicate that tetrandrine decreased cardiac mass in DOCA-salt hypertensive rats through mechanisms that may be associated with the density and the total number of dihydropyridine binding sites, Ca2+ and blood pressure control. Topics: Alkaloids; Animals; Antihypertensive Agents; Benzylisoquinolines; Binding, Competitive; Blood Pressure; Body Weight; Calcium; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Male; Mitochondria, Heart; Organ Size; Radioligand Assay; Random Allocation; Rats; Rats, Sprague-Dawley | 1995 |
Comparison of effects of ACE inhibition with calcium channel blockade on renal disease in a model combining genetic hypertension and diabetes.
The aim of this study was to compare the renal effects of angiotensin converting enzyme (ACE) inhibition with calcium channel blockade in a model combining genetic hypertension with diabetes. Streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). The animals were then randomized to receive no treatment, the ACE inhibitor, perindopril, or the dihydropyridine calcium antagonist lacidipine. Body weight, systolic blood pressure, glycemic control, renal function, and albumin excretion rate (AER) were assessed serially over the 32-week study period. At week 32 the animals were killed and glomerular volume was measured. Both antihypertensive regimens significantly reduced systolic blood pressure in diabetic SHR. There was no significant difference in glycemic control, serum creatinine, or glomerular filtration rate among the three groups at week 32. The ACE inhibitor perindopril significantly reduced AER and glomerular hypertrophy over the 32 weeks, whereas the calcium antagonist lacidipine failed to reduce AER or glomerular hypertrophy. Thus, in contrast to the effects of ACE inhibition, calcium channel blockade with lacidipine, despite significantly reducing blood pressure, failed to reduce renal injury in this model. These results support the hypothesis that antihypertensive regimens may differ in their capacity to protect the diabetic kidney, despite similar effects on systemic blood pressure. Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Indoles; Kidney Diseases; Male; Perindopril; Random Allocation; Rats; Rats, Inbred SHR; Renin | 1995 |
Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice.
S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. Topics: Administration, Oral; Animals; Anticonvulsants; Bemegride; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Electroshock; Female; Injections, Subcutaneous; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pentylenetetrazole; Picrotoxin; Seizures | 1994 |
Cardioprotective actions of potassium channel openers.
The potential cardioprotective effect of two pure potassium channel openers, bimakalim (EMD 52692) and aprikalim (RP 52891), on myocardial ischaemia/reperfusion injury was investigated in barbital-anaesthetized dogs. In a model of reversible ischaemia/reperfusion injury, administration of bimakalim as an intravenous bolus prior to ischaemia or administration of a non-hypotensive dose of aprikalim as a constant intravenous infusion resulted in a reduction in reperfusion contractile dysfunction (myocardial 'stunning') produced by a single 15-min coronary artery occlusion. Administration of aprikalim only during the reperfusion period had no beneficial effect. Similarly, in a model of irreversible ischaemia/reperfusion injury (90 min of coronary artery occlusion followed by 5 h of reperfusion), intravenous infusion of bimakalim at a dose which reduced aortic blood pressure approximately 15-20 mmHg or infusion of aprikalim at a non-hypotensive dose throughout the entire experiment produced a significant reduction in myocardial infarct size. A protective effect of bimakalim was not observed when it was administered during the reperfusion period only. In both the stunned myocardium model as well as the infarcted myocardium model, the beneficial effects of the potassium channel openers could not be attributed to differences in the traditional determinants of the extent of ischaemia/reperfusion injury; area at risk size, oxygen consumption, or collateral blood flow. Furthermore, the anti-ischaemic actions of the potassium channel openers were blocked by pre-treatment with the ATP-dependent potassium (KATP) channel antagonist, glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Animals; Benzopyrans; Dihydropyridines; Disease Models, Animal; Dogs; Female; Glyburide; Male; Myocardial Infarction; Myocardial Stunning; Picolines; Potassium Channel Blockers; Potassium Channels; Pyrans; Vasodilator Agents | 1994 |
Protective effects of benidipine against myocardial damage following ischemia and reperfusion in the isolated perfused rat heart.
We investigated the possible protective effects of benidipine (Coniel), a calcium antagonist, on mechanical dysfunction, metabolic damage and changes in vascular reactivity during ischemia and reperfusion in the Langendorff-perfused rat heart. The responses of perfusion pressure to U-46619, a vasoconstrictor, and acetylcholine, an endothelial-dependent vasodilator, were also determined as indices of the vascular function. Thirty min of reperfusion following 30 min of global ischemia produced contractile failure and the marked release of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). Additionally, the ischemia and reperfusion augmented the vasoconstrictor response to U-46619, and depressed the endothelium-dependent vasodilator response to acetylcholine. These hearts were treated with 1 or 10 nM benidipine from 20 min before ischemia to the beginning of ischemia. While benidipine at 10 nM had a modest negative inotropic action, 1 nM of this drug had minimal depressant effects on the preischemic function. The depressed contractile function after the ischemia was improved, and the increased releases of LDH and CPK were significantly ameliorated by benidipine. Also, benidipine restored the augmented contractile response to U-46619 and preserved the vasodilator response to acetylcholine. These results demonstrate that pretreatment with benidipine prevents myocardial injury following ischemia and reperfusion. The cardioprotective effects of benidipine may in part be due to the protection of vascular reactivity by this drug. Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents | 1994 |
Protective action of lacidipine in cardiac hypertrophy of the spontaneously hypertensive stroke-prone rat: an ultrastructural study.
We investigated the effect on cardiac hypertrophy of a once-daily treatment with lacidipine, at doses that do not reduce systolic blood pressure. Spontaneously hypertensive stroke-prone rats (SHR-SP) were fed a 1% NaCl enriched diet and treated daily by gastric gavage with lacidipine at doses of 0.3, 1, or 3 mg/kg/die or vehicle. At 15 weeks of age the rats were sacrificed. The heart was removed, weighed and processed for transmission electron microscopy, scanning electron microscopy and ultrastructural morphometry. Though the treatment did not reduce systolic blood pressure, heart weight and heart weight/body weight ratio were lower in the lacidipine-treated rats than in those treated with vehicle alone. Medial and subendothelial lesions were visible in coronaries of vehicle-treated SHR-SP but not in animals treated with lacidipine. In the cardiocytes of the lacidipine-treated rats, the myofibrils had a more regular arrangement and the intercalated discs did not show the irregular course and infoldings seen in the vehicle-treated rats. Morphometry showed a significantly higher density of mitochondria in the cardiocytes of lacidipine-treated SHR-SP. Scanning electron microscopy identified a decrease in the width of cardiocytes and in the number and length of lateral branches following lacidipine-treatment. The cardio-protective action of this calcium-antagonist at doses that do not reduce systolic blood pressure is attributable both to its vascular activity and to improvement in cytoplasmic organization of cardiocytes. Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Myocardium; Rats; Rats, Inbred SHR | 1994 |
[The effect of the new amino acid-containing 1,4-dihydropyridine glutapyrone on penicillin-induced focal epileptic activity and convulsions induced by bicuculline and thiosemicarbazide].
The experiments on focal penicillin-induced epileptic activity in the brain cortex (Wistar rats) and bicuculline- and thiosemicarbazide-induced seizures (Icr:Icl mice) showed that the glutapyrone possessed a significant antiepileptic activity. As previously shown, that glutapyrone has an influence on 45Ca2+ uptake by rat cortical synaptosomes (evoked by K+ depolarization) as compared with nifedipine and nimodipine, and it was effective in pentylenetetrazol-induced seizures in rats and mice. The mechanism of action of convulsants is associated with the disturbance of different links of GABAergic inhibition. It is suggested that the antiepileptic effects of glutapyrone are realized at least in part by the participation of GABAergic system. Topics: Animals; Anticonvulsants; Bicuculline; Convulsants; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsies, Partial; Glutamates; Male; Mice; Mice, Inbred ICR; Penicillins; Rats; Rats, Wistar; Seizures; Semicarbazides | 1993 |
[Effect of palonidipine hydrochloride (TC-81), a new dihydropyridine derivative, on various myocardial ischemic models].
The antianginal effects of palonidipine, a novel 1,4-dihydropyridine derivative, and nifedipine on various myocardial ischemic models were compared. (1) Palonidipine at 0.5 mg/kg, p.o. significantly inhibited vasopressin-induced ST depression of ECG in Donryu rats. This activity was about 5 times more potent than that of nifedipine and was long-lasting. (2) Palonidipine at 1 mg/kg, i.d. significantly inhibited ST depression induced by isoproterenol in Wistar rats. This activity of TC-81 was more potent than that of nifedipine. (3) Palonidipine at 3 micrograms/kg, i.v. produced an increase in regional myocardial tissue blood flow in the ischemic region of chronic coronary artery occluded dogs. (4) In isolated dog coronary artery, palonidipine at a concentration of 10(-10) M or greater inhibited the amplitude of 3,4-DAP-induced cyclic contractions in a concentration-dependent manner. This activity was 10-30 times more potent than that of nifedipine. (5) An intracoronary injection of endothelin (30 pmol/kg) reduced the coronary blood flow, subepicardial tissue blood flow, and subepicardial pH in anesthetized dogs. The ST elevation of ECG over 0.1 mV also occurred in 8 of 10 cases. In all the cases, ventricular extrasystoles were noted, and 9 out of 10 animals died. Pretreatment with palonidipine (3 micrograms/kg, i.v.) inhibited endothelin-induced ischemic changes, with a potency greater than that of nifedipine. These results suggest that palonidipine may be useful for the therapy of angina-pectoris. Topics: Angina Pectoris; Animals; Calcium Channel Blockers; Coronary Circulation; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Female; In Vitro Techniques; Male; Nifedipine; Rats; Rats, Wistar; Vasoconstriction | 1993 |
Platelet-derived growth factor gene expression in the kidney of malignant hypertension.
To examine the pathogenetic role of platelet-derived growth factor (PDGF) in hypertensive kidney damage, we studied the gene expression of PDGF A-chain and B-chain in an animal model of malignant hypertension. Experimental malignant hypertension induced by unilateral nephrectomy combined with deoxycorticosterone and salt loading in the spontaneously hypertensive rat resulted in severely elevated blood pressure and renal histological damage, characterized by necrotizing vasculitis. Using reverse transcription-polymerase chain reaction analysis followed by Southern blot analysis, we observed that PDGF B-chain gene expression was increased in the kidney of experimental malignant hypertension and was correlated with the severity of glomerular damage, while PDGF A-chain gene expression was unaffected. Antihypertensive treatment with manidipine reduced glomerular damage and a decreased gene expression of PDGF B-chain. These results suggest that PDGF B-chain may have a role in mediating hypertensive kidney damage. Topics: Animals; Base Sequence; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Gene Expression; Hypertension, Malignant; Kidney; Molecular Sequence Data; Nitrobenzenes; Piperazines; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; RNA-Directed DNA Polymerase | 1992 |
Manidipine attenuates a progressive renal injury in remnant kidneys of rats.
The effects of a calcium antagonist, manidipine, on the outcome of the remnant kidney model of chronic renal failure in rats were studied. After 5/6 nephrectomy (5/6 Nx), rats were assigned to one of the following groups, and fed: Nx without manidipine, group 1; diet with 0.01% manidipine, group 2. A sham 5/6 Nx group was also included as the control. Each diet contained the same calories (3.44 kcal/g) and protein (25% casein). Increased systolic blood pressure seen after 8 weeks postablation was less with manidipine in group 2. Group 2 also had significantly less proteinuria. By 12 weeks postablation, group 1 showed severe parenchymal damage, characteristic of end-stage renal pathology. These changes were prevented by manidipine. The percentage of glomeruli with severe structural damage including sclerosis and/or hyalinosis, arbitrarily defined as glomerular sclerosis index (GSI) was significantly less in group 2 (41 +/- 11%) compared with group 1 (58 +/- 10%). Tubulointerstitial injury (TII) was also less in group 2 (29.1 +/- 9.1%) compared with group 1 (45.1 +/- 10.3%). Sham-Nx control group without manidipine showed normal renal morphology (GSI, 0.2 +/- 0.6, TII, 3.8 +/- 1.0). These results indicate that manidipine attenuates the development of end-stage renal pathology in the remnant kidney model of chronic renal failure in rats. The mechanism(s) remains to be elucidated. Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Kidney Failure, Chronic; Male; Nephrectomy; Nitrobenzenes; Piperazines; Rats; Rats, Inbred F344 | 1992 |
Vascular protection of lacidipine in salt-loaded Dahl-S rats at nonsustained antihypertensive doses.
The aim of this study was to characterize the antihypertensive and vasoprotective properties of lacidipine in salt-loaded Dahl-S rats, a suitable animal model of malignant hypertension. After 9 weeks of a high (8%) sodium chloride (NaCl) diet, 80% of the untreated Dahl-S rats died (20% survival rate) whereas a 100% survival rate was observed with chronic treatment with lacidipine at doses of 0.1 (equivalent to the recommended dose in humans), 0.3, 1, and 10 mg/kg once daily by gastric gavage. The most interesting results included the following: (a) Only the highest dose tested (10 mg/kg once daily) was able to control the increase in blood pressure, which was measured 24 h after the preceding administration of drug, yet a 100% survival rate was maintained. (b) There appeared to be prevention of brain lesions, which is very likely the cause of the survival of all of the lacidipine-treated rats in this study. (c) A clear dose-related vascular protection was observed in other tissues. In conclusion, lacidipine protects against the vascular damage and concomitant increase in mortality of salt-loaded Dahl-S rats even at doses that do not adequately control the development of hypertension. Topics: Administration, Oral; Animals; Blood Pressure; Brain; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Fundus Oculi; Hypertension, Malignant; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary | 1991 |
Prevention of stroke and brain damage with calcium antagonists in animals.
In a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery [MCAO]), various 1,4-dihydropyridine calcium antagonists have been shown to attenuate brain damage and the resultant functional impairment when administered after MCAO. Dose-response curves reveal that isradipine is one of the most potent and efficacious representatives of this class of compounds, reducing the infarct size by more than 60%. These results suggest that isradipine, when administered shortly after stroke onset, may have beneficial effects in patients suffering from brain ischemia. When isradipine is used to normalize the high blood pressure in spontaneously hypertensive rats, it will, in addition, also protect the brain from damage engendered by a subsequent stroke. This is not the case if blood pressure is controlled with a calcium antagonist which does not cross the blood-brain barrier, suggesting that the brain protection seen with isradipine is not due to blood pressure normalization. Isradipine, when used as an antihypertensive, appears to have an additional beneficial effect within the brain itself. As high blood pressure is a major risk factor for stroke, such an additional benefit with isradipine would be particularly valuable in antihypertensive therapy. Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Isradipine; Male; Prognosis; Pyridines; Rats; Rats, Inbred SHR | 1991 |
Gingival hyperplasia in rats induced by oxodipine--a calcium channel blocker.
Oxodipine, a new calcium channel blocker, induced gingival hyperplasia in rats. This is the first time that a calcium channel blocker has been documented as resulting in gingival hyperplasia in rats. In contrast to diphenylhydantoin, the hyperplastic changes induced by oxodipine were not precipitated by any prior irritation. The histology consisted of purely fibroblastic proliferation without infiltrate of inflammatory cells. Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Female; Gingival Hyperplasia; Male; Rats; Rats, Inbred F344 | 1990 |
Oxodipine-induced gingival hyperplasia in beagle dogs.
Topics: Animals; Dihydropyridines; Disease Models, Animal; Dogs; Gingival Hyperplasia | 1990 |
A non-human primate model for the study of oral iron chelators.
Recent studies have demonstrated that parenteral deferroxamine can prolong life in patients with iron overload. We have developed a non-human primate model of iron overload and have accurately determined negative iron balance in parenteral and oral studies of deferroxamine and a new chelator, desferrithiocin. Cebus monkeys were loaded with iron dextran (10 mg/kg twice weekly) until their serum contained a transferrin saturation greater than 75%, and (in two animals) liver biopsies showed iron loading. When complete iron balance studies were performed at this time, basal iron balance was -53 +/- 11 micrograms (N = 4), providing a low background for provocative studies. Iron balance was determined for intramuscular (N = 2) and oral (N = 3) deferroxamine, as well as intramuscular (N = 1) and oral (N = 4) desferrithiocin. The pattern of iron excretion after parenteral deferroxamine strongly resembled that of the iron-loaded, transfused human. Desferrithiocin was found to have significant activity as an oral chelator. This Cebus monkey model accurately determines negative iron balance and readily permits precise comparison of iron chelators given parenterally or orally. This model may offer an important step between rodent and human trials of promising new iron chelators. Topics: Administration, Oral; Animals; Cebus; Deferoxamine; Dihydropyridines; Disease Models, Animal; Injections, Intramuscular; Iron; Iron Chelating Agents; Thiazoles | 1989 |
Morphine withdrawal in cortical slices: suppression by Ca2+-channel inhibitors of abstinence-induced [3H]-noradrenaline release.
1. The effects of morphine withdrawal were evaluated in vitro by monitoring the actions of naloxone on the depolarization-induced release of [3H]-noradrenaline (NA) in cortical slices taken from naïve or dependent rats. The effects of dihydropyridine molecules acting on Ca2+-channels (nimodipine and Bay K 8644) were also studied in this model. 2. Naloxone (10(-8)-10(-5) M) dose-dependently enhanced the K+ induced release of [3H]-NA in slices taken from dependent rats, but failed to modify the [3H]-NA release from 'naïve' slices. 3. The naloxone-induced potentiation of release was significantly reversed by nimodipine (10(-8)-10(-6) M). These doses of nimodipine did not change [3H]-NA release (both basal and K+ induced) in preparations obtained from naïve rats. 4. Bay K 8644 potentiated the K+-induced [3H]-NA release from cortical slices taken from naïve rats to a similar extent as that of naloxone in dependent rats. 5. These results suggest that the naloxone potentiation of the depolarization-induced [3H]-NA release in slices taken from dependent rats may be considered a model of morphine withdrawal in vitro. In this model dihydropyridine Ca2+-channel antagonists suppress morphine-withdrawal effects in a similar manner to observations made in vivo. Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium; Cerebral Cortex; Dihydropyridines; Disease Models, Animal; In Vitro Techniques; Ion Channels; Morphine; Naloxone; Nimodipine; Norepinephrine; Rats; Substance Withdrawal Syndrome; Tritium | 1988 |
The antithrombogenic in vivo effects of calcium channel blockers in experimental thrombosis in mice.
A new model of thrombotic challenge, well suited for screening agents and which acts primarily against platelet thromboembolism, has been used to test the in vivo anti-platelet effects of four calcium channel blockers (CCB). An i.v. injection of a mixture of collagen plus epinephrine (15 micrograms and 1.8 micrograms/mouse, respectively) was given to male mice. 94% control mice died or remained paralyzed for more than 15 minutes. The dihydropyridine agents, CRE-223 and Nifedipine, were highly protective against experimental thrombosis, whereas Verapamil had a weaker and much shorter effect and, on the other hand, Diltiazem had no protective effect over a range of doses. The activity on both dihydropyridines lasted for seven hours or even longer. Topics: Animals; Calcium Channel Blockers; Collagen; Dihydropyridines; Diltiazem; Disease Models, Animal; Dose-Response Relationship, Drug; Epinephrine; Male; Mice; Mice, Inbred Strains; Nifedipine; Thrombosis; Time Factors; Verapamil | 1987 |